CZ563490A3 - Process for preparing taxol and oxazinone as intermediate for the preparation - Google Patents
Process for preparing taxol and oxazinone as intermediate for the preparation Download PDFInfo
- Publication number
- CZ563490A3 CZ563490A3 CS905634A CS563490A CZ563490A3 CZ 563490 A3 CZ563490 A3 CZ 563490A3 CS 905634 A CS905634 A CS 905634A CS 563490 A CS563490 A CS 563490A CZ 563490 A3 CZ563490 A3 CZ 563490A3
- Authority
- CZ
- Czechia
- Prior art keywords
- ethyl acetate
- solution
- mmol
- alkyl
- taxol
- Prior art date
Links
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 50
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 48
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title claims abstract description 42
- FBXGQDUVJBKEAJ-UHFFFAOYSA-N 4h-oxazin-3-one Chemical compound O=C1CC=CON1 FBXGQDUVJBKEAJ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- -1 t-butoxy Chemical group 0.000 claims description 62
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 12
- 230000003213 activating effect Effects 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 150000002148 esters Chemical group 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical group [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Chemical group CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000001302 tertiary amino group Chemical group 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract description 30
- 125000003342 alkenyl group Chemical group 0.000 abstract description 20
- 125000000304 alkynyl group Chemical group 0.000 abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 18
- 239000001257 hydrogen Substances 0.000 abstract description 17
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 4
- 125000005741 alkyl alkenyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 327
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 156
- 239000000243 solution Substances 0.000 description 83
- 239000000203 mixture Substances 0.000 description 54
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 52
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- 239000000741 silica gel Substances 0.000 description 39
- 229910002027 silica gel Inorganic materials 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- 229910052938 sodium sulfate Inorganic materials 0.000 description 38
- 235000011152 sodium sulphate Nutrition 0.000 description 38
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000001953 recrystallisation Methods 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 125000004423 acyloxy group Chemical group 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 229910000365 copper sulfate Inorganic materials 0.000 description 12
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 12
- 125000001424 substituent group Chemical class 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 125000004043 oxo group Chemical group O=* 0.000 description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 125000005133 alkynyloxy group Chemical group 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 150000004579 taxol derivatives Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 3
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YTBSMLRVFPHDOB-ZJUUUORDSA-N [(3s,4r)-2-oxo-4-phenylazetidin-3-yl] acetate Chemical compound N1C(=O)[C@@H](OC(=O)C)[C@H]1C1=CC=CC=C1 YTBSMLRVFPHDOB-ZJUUUORDSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- XSYLUBKWRZCOQP-QIWLAUOQSA-N (3s,4r)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound N1([C@@H]([C@@H](C1=O)OC(C)OCC)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 XSYLUBKWRZCOQP-QIWLAUOQSA-N 0.000 description 2
- FBZSDKXFQUKDLD-SFYZADRCSA-N (3s,4r)-3-hydroxy-4-phenylazetidin-2-one Chemical compound N1C(=O)[C@@H](O)[C@H]1C1=CC=CC=C1 FBZSDKXFQUKDLD-SFYZADRCSA-N 0.000 description 2
- QMIZAASILSBRMQ-UHFFFAOYSA-N 5-(1-ethoxyethoxy)-2-[(2-methylpropan-2-yl)oxy]-4,4-diphenyl-5h-1,3-oxazin-6-one Chemical compound CCOC(C)OC1C(=O)OC(OC(C)(C)C)=NC1(C=1C=CC=CC=1)C1=CC=CC=C1 QMIZAASILSBRMQ-UHFFFAOYSA-N 0.000 description 2
- NNKCQQPVYUHCHF-UHFFFAOYSA-N 5-(1-ethoxyethoxy)-2-[(2-methylpropan-2-yl)oxy]-4-phenyl-4,5-dihydro-1,3-oxazin-6-one Chemical compound N1=C(OC(C)(C)C)OC(=O)C(OC(C)OCC)C1C1=CC=CC=C1 NNKCQQPVYUHCHF-UHFFFAOYSA-N 0.000 description 2
- FEYQACXBKHREMV-UHFFFAOYSA-N 5-(1-ethoxyethoxy)-5-methyl-2,4-diphenyl-4h-1,3-oxazin-6-one Chemical compound O1C(=O)C(OC(C)OCC)(C)C(C=2C=CC=CC=2)N=C1C1=CC=CC=C1 FEYQACXBKHREMV-UHFFFAOYSA-N 0.000 description 2
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- YWTCDTFWPNSBIU-SJORKVTESA-N [(3s,4r)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl] acetate Chemical compound C1=CC(OC)=CC=C1N1C(=O)[C@@H](OC(C)=O)[C@H]1C1=CC=CC=C1 YWTCDTFWPNSBIU-SJORKVTESA-N 0.000 description 2
- 125000003302 alkenyloxy group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 125000005587 carbonate group Chemical group 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000006038 hexenyl group Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000005980 hexynyl group Chemical group 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- UPUNPNQSFNXVJX-UHFFFAOYSA-N 1-hydroxy-4-phenylazetidin-2-one Chemical compound C1C(=O)N(O)C1C1=CC=CC=C1 UPUNPNQSFNXVJX-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- WKIOQNPKWHHOOO-UHFFFAOYSA-N 2,5-dihydrooxazin-6-one Chemical compound O=C1CC=CNO1 WKIOQNPKWHHOOO-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- PVZFSFXWKJSMLV-UHFFFAOYSA-N 3-(1-ethoxyethylamino)-2-hydroxy-3-phenylpropanoic acid Chemical compound C(C)OC(C)NC(C(O)C(=O)O)C1=CC=CC=C1 PVZFSFXWKJSMLV-UHFFFAOYSA-N 0.000 description 1
- FQOAQSKCRBQNAS-UHFFFAOYSA-N 3-[1-ethoxyethyl-[(2-methylpropan-2-yl)oxycarbonyloxy]amino]-2-hydroxy-3,3-diphenylpropanoic acid Chemical compound C(C)(C)(C)OC(=O)ON(C(C(O)C(=O)O)(C1=CC=CC=C1)C1=CC=CC=C1)C(C)OCC FQOAQSKCRBQNAS-UHFFFAOYSA-N 0.000 description 1
- HOPLWKIYJSEHOL-UHFFFAOYSA-N 3-[benzoyloxy(1-ethoxyethyl)amino]-2-hydroxy-2-methyl-3-phenylpropanoic acid Chemical compound C(C1=CC=CC=C1)(=O)ON(C(C(O)(C(=O)O)C)C1=CC=CC=C1)C(C)OCC HOPLWKIYJSEHOL-UHFFFAOYSA-N 0.000 description 1
- MWKMQPSNTJCASD-UHFFFAOYSA-N 4-phenylazetidin-2-one Chemical compound N1C(=O)CC1C1=CC=CC=C1 MWKMQPSNTJCASD-UHFFFAOYSA-N 0.000 description 1
- WSKFEANLIDSKSN-UHFFFAOYSA-N 5-(1-ethoxyethoxy)-2,4-diphenyl-4,5-dihydro-1,3-oxazin-6-one Chemical compound O1C(=O)C(OC(C)OCC)C(C=2C=CC=CC=2)N=C1C1=CC=CC=C1 WSKFEANLIDSKSN-UHFFFAOYSA-N 0.000 description 1
- YWLXLRUDGLRYDR-LUPIKGFISA-N 7-epi-10-deacetylbaccatin iii Chemical group O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-LUPIKGFISA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- GDHOCBKFCINUPU-UHFFFAOYSA-N CCCCOC1=NC(C(C(=O)O1)OC(C)OCC)C2=CC=CC=C2 Chemical compound CCCCOC1=NC(C(C(=O)O1)OC(C)OCC)C2=CC=CC=C2 GDHOCBKFCINUPU-UHFFFAOYSA-N 0.000 description 1
- HZEJCGXSBOAQSQ-UHFFFAOYSA-N CCOC(C)OC1C(N=C(OC1=O)C(C)(C)C)C2=CC=CC=C2 Chemical compound CCOC(C)OC1C(N=C(OC1=O)C(C)(C)C)C2=CC=CC=C2 HZEJCGXSBOAQSQ-UHFFFAOYSA-N 0.000 description 1
- SVRLDWIWUZVVPC-UHFFFAOYSA-N CCOC(C)OC1C(N=C(OC1=O)C2=CC3=CC=CC=C3C=C2)C4=CC=CC=C4 Chemical compound CCOC(C)OC1C(N=C(OC1=O)C2=CC3=CC=CC=C3C=C2)C4=CC=CC=C4 SVRLDWIWUZVVPC-UHFFFAOYSA-N 0.000 description 1
- QTZHTLOZCGCIDX-UHFFFAOYSA-N CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC3=CC=CC=C32)C4=CC=CC=C4 Chemical compound CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC3=CC=CC=C32)C4=CC=CC=C4 QTZHTLOZCGCIDX-UHFFFAOYSA-N 0.000 description 1
- IZLAQBBCNJPQBV-UHFFFAOYSA-N CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC=C2)C(C)(C)C Chemical compound CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC=C2)C(C)(C)C IZLAQBBCNJPQBV-UHFFFAOYSA-N 0.000 description 1
- BLCZYUZBMNGXAH-UHFFFAOYSA-N CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC=C2)C3=CC4=CC=CC=C4C=C3 Chemical compound CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC=C2)C3=CC4=CC=CC=C4C=C3 BLCZYUZBMNGXAH-UHFFFAOYSA-N 0.000 description 1
- VUMOGUADSBOYLK-UHFFFAOYSA-N CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC=C2)C3=CC=C(C=C3)OC Chemical compound CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC=C2)C3=CC=C(C=C3)OC VUMOGUADSBOYLK-UHFFFAOYSA-N 0.000 description 1
- QYEKIVAVUXGBDH-UHFFFAOYSA-N CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC=C2)C3=CC=CC4=CC=CC=C43 Chemical compound CCOC(C)OC1C(N=C(OC1=O)C2=CC=CC=C2)C3=CC=CC4=CC=CC=C43 QYEKIVAVUXGBDH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 240000007182 Ochroma pyramidale Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 241001116500 Taxus Species 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229930014667 baccatin III Natural products 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- HYXXTUOWDIJLPS-UHFFFAOYSA-N copper;sulfane Chemical compound S.[Cu+2] HYXXTUOWDIJLPS-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000005912 ethyl carbonate group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical group C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 125000002456 taxol group Chemical group 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/84—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing rings with more than eight members
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- General Chemical & Material Sciences (AREA)
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- Veterinary Medicine (AREA)
- Epoxy Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Oblast techniky
Vynález se týká způsobu přípravy taxolu s protirakovinovou účinností a oxazinonu jakožto meziproduktu pro tuto přípravu.
Dosavadní stav techniky
Taxany jsou skupinou terpenů, které věnují velkou pozornost jak biologové tak chemici. Taxol, člen této skupiny, je slibným chemoterapeutickým činidlem rakoviny se širokým spektrem protiKekdou-γ , , . , , leukemické a inhibující aktivity. Taxol má následující strukturní vzorec:
Vzhledem k této slibné aktivitě se provádějí jak ve Francii tak ve Spojených státech amerických klinické testy s taxolem,
Taxol se pro tyto klinické testy v současné době získává z kůry několika druhů tisu. Taxol se však v kůře těchto pomalu rostoucích, stále zelených stromů vyskytuje pouze v nepatrných množstvích. Z toho vypl|vají značné obavy, že tyto omezené zásoby taxolu nebudou postačovat požadavkům. Proto se chemici v posledních letech snaží vyvinout přijatelný způsob pro přípravu taxolu. Až dosud nebyly výsledky plně uspokojivé.
Jednou ze syntetických cest, které byla navržena, je syntéza t ^acyklického taxanového jádra z obchodně dostupných chemikálií. Syntéza taxolu příbuzného taxufinu byla popsána Holtonem a spol., JAGS.110, 6558 (1988)·. Navzdory pokroku, který, tento postup přináší, konečné úplná syntéza taxolu je eefeo pravděpodobně vícestupňový, zdlouhavý a nákladný postup.
Alternativní postup přípravy taxolu byl popsán -Greeneis a spol,, JACS 110, 5917 (1988). Tento postup používá 1 O-deacetyl-bakatinu III příbuzného taxolu následujícího vzorce:
1O-Deacetyl-bakatin III je snadněji dostupný než taxol, nebot jej lze získat z listů Taxus baccata. Způsobem podle Greenea a spol, se 1O-deacetyl-bakatin III převede na taxol připojením acetylové skupiny na atom uhlíku a připojením (^-amidoesterového postranního řetězce na atom uhlíku esterifikací alkoholu na atomu uhlíku C^ (^-amidokarboxylovou kyselinou. I když tento postup vyžaduje rela
-3tivně jen několik stupňů, je syntéza fb -amidokarboxylové části mnohostupňový postup, který probíhá s nízký® výtěžkea. kondenzační reakce je zdlouhavá a probíhá rovněž s nízký» výtěžke®. ^ato kondenzační reakce je však klíčový® stupně» syntézy, který je potřebný při každé uvažované syntéze taxolu nebo biologicky aktivního derivátu taxolu, neboí Wani a spol., JACS 93,2325 (1971) ukázali, že příto»nost /5-amidoesterového postranního řetězce na ato»u uhlíku je pro protinádorovou účinnost potřebné.
Hlavní» probléaea při syntéze /axolu a dalších potenciál nich protinádorových činidel je nedostatek snadno dostupných jednotek/částí, které by se snadno napojily na atoa kyslíku na atomu za vzniku f^-amidoesterového postranního řetězce. Vyvinutí takové jednotky a způsobu jejího napojení ve vysoké» výtěžku by usnadnilo syntézu taxolu a podobných protinádorových činidel, které aají modifikovanou řadu substituentů na jádře nebo »odifikovaný postranní řetězec na atomu uhlíku Cjj. Tuto potřebu naplňuje objev nové, snadno dostupné chemické jednotky prekurzoru postranního řetězce a účinný způsob jeho napojení na atom kyslíku na atomu uhlíku C,,.
Úkolem,předloženého vynálezu patří—_je^získání prekurzoru postranního řetězce pro syntézu taxolů a získání způsobu připojení prekurzoru postranního řetězce v relativně vysokém výtěžku, Čímž se získá meziprodukt taxolu.
3a
Podstata vynálezu
ve kterém je
Ri fenyl, <x- nebo p-naftyl, Ci.ealkyl nebo t-butoxyskupina,
Rz fenyl, cc- nebo p-naftyl, Ci-ealkyl nebo p-met boxy f eny 1,
Ph fenyl,
Ac acetyl spočívá podle vynálezu v tom, ěe se oxazinon obecného vzorce I
VY Ν'^ΛθΠ.
( I) ve kterém Ri a Rz mají shora uvedené významy a ve kterém je R3 skupina chránící hydroxyskupinu, uvede ve styk s alkoholem vzorce III
HOlIltl
< III) kde Ph a Ac mají shora uvedený význam, v přítomnosti aktivačního činidla a získaný p-amidoester se hydrolyzuje.
Podstatou vynálezu je také prekursor vedlejšího postranního ře těžce, meziprodukt pro přípravu taxolu, oxazinon obecného vzorce I
kde Rj fce aryl, heteroaryl, alkyl, alkenyl, alkinyl, nebo OH?, kde Ηγ je alkyl, alkenyl, alkinyl, aryl nebo heteroaryl, Bg a R^ jsou nezávisle na sobě vybrány ze souboru, který tvoří vodík, alkyl, alkenyl, alkinyl, aryl, heteroaryl a-ΟΒθ, kde Rg je alkyl, alkenyl, alkinyl, aryl, hetero aryl nebo chránící skupina hydroxylové skupiny a Rj a Rg jsou nezávisle na sobě vybrány ze souboru, který tvoří vodík, alkyl, alkenyl, alkinyl, aryl a heteroaryl·
Podložený vynález-be Ldké LýKá—způsubfpřípravý produktů taxolu,který je charakterizován tÍBv-áeree uvede do styku alkohol s oxazinonen obecného vzorce I za přítomnosti dostatečného luioáství aktivačního činidla pro vyvolání reakce oxaztnonu s alkoholem za vzniku p~amidoesteru, který^může být použit jako meziprodukt při syntéze taxolu.
-5•BalSI předměty a vlastnooti předloženého Vynález1 blíže objasňuje j následující1 popis.
•Předložený vynález se týká oxazinonu obecného vzorce I a jeho derivátů.
(I)
V uvedené» vzorci, jak je uvedeno výSe Ej je aryl, heteroaryl, alkyl, alkenyl, alkinyl nebo-OR?, kde Βγ je alkyl, alkenyl, alkinyl, aryl nebo heteroaryl, Eg a jsou nezávisle na sobě vybrány ze souboru, který tvoří alkyl, alkenyl, alkinyl, aryl, heteroaryl a-ΟΒθ, kde Βθ je alkyl, alkenyl, alkinyl, aryl, heteroaryl, nebo chránící sku pina hydroxylové skupiny, a Bj a Rg jsou nezávisle na sobě vybrány ze souboru, který tvoří vodík, alkyl, alkenylj alkinyl, aryl a heteroaryl.
Výhodně aá oxazinon obecného vzorce I vzorec IA
(IA) «3
-6kde Rj, Hj a Βθ mají výše definovaný význeua· Ne jvýhodněji je Rg ethoxyethyl nebo 2,2,2-trichlorethoxymethyl. Vzorec nejvýhodnějáího oxazinonu, ve které» Rj a R^ j60u fenyl, R^ je vodík a R2 je“ORg, kde Bg je ethoxyethyl je uveden déle:
Ph «3 5 4 >z
O5'\ (II)
OEE
Ph
V souladu s pravidly IUPAC, je název oxazinonu vzorce II 2,4-difenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6on.
•Podle předloženého vynálezu se připravují meziprodukty taxolu, přírodního taxolu a taxolů, nevyskytujících se v přírodě, mající následující vzorec:
-7kde
A a B nezávisle na sobě znamenají vodík nebo nižší alkanoyloxyskupinu, alkenyloxyskupinu, alkinoyloxyskupinu nebo aryloyloxyskupinu nebo
A a B spolu tvoří oxoskupinu,
L a D nezávisle na sobě znamenají vodík nebo hydroxylovou skupinu nebo nižší alkanoyloxyskupinu, alkenoyloxyskupinu, alkinoyloxyskupinu nebo aryloyloxyskupinu,
E a F nezávisle na sobě znamenají vodík nebo nižší slkanoyloxyskupinu, alkenyoloxyskupinu, alkinoyloxyskupinu nebo aryloyloxyskupinu nebo
E a F spolu tvoří oxoskupinu,
G znamená vodík nebo hydroxylovou skupinu nebo nižší alkanoyloxyskupinu, alkenoyloxyskupinu, alkinoyloxyskupinu nebo aryloyloxyskupinu, nebo
G a Ič spolu tvoří oxoskupinu nebo methylen nebo
G a 1.Í spolu tvoří oxiranový kruh nebo
M a F spolu tvoří oxetanový kruh,
J je vodík, hydroxylovó skupina nebo nižší alkanoyloxyskupina, .alkenoyloxyskupina, alkinoyloxyskupir.a nebo arylcyloxysku pina nebo
I je vodík, hydroxylovó skupina nebo nižší alkanoylcxyskupina, alkenoyloxyskupina, alkinoyloxyskupina nebo aryloyioxy s kup i na, ne b o
I a J spolu tvoří oxoskupinu a
K je vodík, hydroxylovó skupina nebo nižší alkoxyskupina, alkanoyloxyskupina, alkenoyloxyskupina, alkinoyloxyskupina nebo aryloyloxyskupina a
P a nezávisle na sobe znamenají vodík nebo nižší alkanoyl-8oxyskupinu, alkenoyloxyskupinu, alkinoyloxyekupinu nebo aryloyloxyskupinu nebo
P a Q společně tvoří oxoskupinu a
S a T nezávisle na sobě znamenají vodík nebo nižší alkanoyloxyskupinu, alkenoyloxyskupinu, alkinoyloxy skupinu nebo aryloyloxyskupinu, nebo
S a T spolu tvoří oxoskupinu a
U a V nezávisle na sobě znamenají vodík nebo nižSí alkyl, alkenýl, alkinyl, aryl, nebo substituovaný aryl a
W znamená aryl, substituovaný aryl, nižší alkyl, alkenyl, > alkinyl^ alkoxy nebo aryloxy.
laxolové alkylové skupiny, buá samotné nebo s různými substituenty definované výše výhodně představují nižší alkyl, obsahující od jednoho do šesti atomů uhlíku v základním řeo tězci a až 1 0 atomy uhlíku· Mohou mít přímý nebo rozvětvený řetězec a zahrnují methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terč.butyl, aryl, hexyl a podobně.
iaxologé alkenylové skupiny, buá samotné nebo s různými substituenty, definované výše jsou výhodně nižší alkenyl, obsahující výhodně od dvou do šesti atomů uhlíku v základním řetězci a až 10 atomů uhlíku. Mohou mít přímý nebo rozvětvený řetězec a zahrnují ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl a podobně.
Taxolové alkinylové skupiny, buá samotné nebo s různými substituenty definovanými výše výhodně představují nižší alkinyl, obsahující od dvou do šesti atomů uhlíku v základním řetězci a až 10 atomů uhlíku. Mohou mít přímý nebo roz-světvený řetězec a zahrnují ethinyl, propinyl, butinyl, isobutinyl, aryl, hexinyi a podobné skupiny'·.
Příklady alkanoyloxyskupiny zahrnují acetátovou, propio nótovou, butyrétovou, valerátovou, isobutyrátovou a podobné skupiny. wejvýhodnější skupinou z alkanoyloxyskupin je acetótová skupina.
Taxolové arylové skupiny, bučí samotné nebo s různými substituenty obsahují od 6 do 10 atomů uhlíku a zahrnují fenyl, -nafty1 nebo fb-naftyl atd.. Substituenty zahrnují alkanoylcxyskupinu, hydrcxylovcu skupinu, halogen, alkylovou skupinu, arylovou skupinu, alkenylovou skupinu, acylovou skupinu, acyloxyskupinu, nitroskupinu, aminoskupinu, amidoskupinu atd.. Kejvýhodnějším arylem je fenyl.
Jak je definováno výše, výraz aryloyloxy” zahrnuje aromatické heterocyklické skupiny, výraz aryl” zahrnuje jakoukoliv sloučeninu mající aromatický kruh, který neobsahuje heteroatom á výraz heteroaryl zahrnuje jakoukoliv sloučeninu, mající aromatický kruh, která obsahuje heteroatom.
Výhodné významy substituentů A,B,D,L,E,F,G,K,I,J,K,P, Q,S,T,U,V a W jsou vyjmenovány dále v tabulce I.
Ή >3 ο
>
Ρ <—I 3
3 OJ
Μ Ή >3 >3
Ο Ο > >
Ρ -Ρ
OAc
27
Způsobem podle vynálezu se oxazinon obecného vzorce I převede na /3 -amidoestery za přítomnosti alkoholu a aktivačního činidla, výhodně terciárního aminu jako je triethylamin, diisopropylethylamin, pyridin, N-methylimidazol a
4-dimethylaminopyridin (DMAP). Například oxazinony obecného vzorce I reagují se sloučeninami, majícími taxanové tetracyklické jádro a hydroxylovou skupinu na C^, za přítomnosti
4-dimethylatninopyridinu (DMAP), za vzniku látek, majících /3 -amidoesterovou skupinu na C^.
Nejvýhodněji je alkoholem 7-O-triethylsilylbakatin obecného vzorce III, který může být získán postupem popsaným Greenem a spol. v JACS 110, 5917 (19M) nebo jinými způsoby. Jak uvádí Greene a spol., 10-deacetylbakatin se převede na 7-0-triethylsilylbakatin vzorce III podle následujícího schematui
-1 6-
1 CCÍHs)3Sl| ,C,H5N
2. CHjCOCIzC5HsN
C1
a, R-H b, r-coch3
Podle opti mali zovanych podmínek reaguje 10-deacetvlbakatin obecného vzorce lil se 20 ekvivalenty (Λ^ΐJI při 23 3 pod atxosfér-u argenu po 20 hodin z<^ cříť'mn ό z 1
r.i pvridi nu/ir.r.ol 1 .L-rfeť^cetvlbaka tinu vzorce Ι1Σ za vzniku
7-triethvleiivi-1ú-deacet^ibakatinu vzorce 111 reakčního produktu ve výtěžku 64 až 66 o ne ční
tžžku 86 % (31b). Gre--ne a spoi. v JAGS 110, 59>7 až 5916 (1968).
Jak ie uvolen·'' v následu iícím. reakčním schématu, může 7-C-triethvls1Ivl-bakatin vzorce 111 (31b) reagovat s oxazinon^-m podle přeiložerYho wnsiftzu při teplot* místnosti za vzni ku taxolovóho meziproduktu, ve které® jsou C-7 a C-2 ' hvdrcxvlov^skupí nv chťénór.y triethvisiIviovými a ethoxyethylovými
-17chrénícími skupinami. Tyto skupiny pak jsou hydrolyzovány za mírných podmínek, takže se nenaruší esterová vazba nebo substí tuenty taxolu. Syntéza taxolu z oxazinonu 2 se provádí následujícím způsobem:
31b
TAXOL
18I když uvedené schéma je vedeno na syhtézu přírodního taxolu, je možno je použít s modifikacemi buď oxazínonu nebo tetracyklického alkoholu, který může být odvozen od přírodních nebo nepřírodních zdrojů, pro přípravu dalších syntetických taxolů v souladu s předloženým vynálezem.
Alternativně může být oxazinon obecného vzorce I převeden na ^-amidoester za přítomnosti aktivačního činidla a alkoholu jiného než je 7-0-triethylsilyl-bakatin III za vzniku taxolových meziproduktů. Syntéza taxolu může být provedena za použití taxolových meziproduktů podle vhodného reakčního schématu.
Oxazinonové alkylové skupiny; buď samotné nebo s různými substituenty definovanými výše, jsou nižší alkylové skupiny obsahující od jednoho do šesti atomů uhlíku v základním řetězci a až 15 atomů uhlíku. Mohou mít přímý nebo rozvětvený řetězec a zahrnují methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terc.butyl, aryl, hexyl a podobné skupiny.
Oxazinonové alkenylové skupiny, buď samotné nebo s různými výše definovanými substituenty výhodně představují nižší alkenyl obsahující od dvou do šesti atomů uhlíku v základním řetězci a až 15 atomů uhlíku. Mohou mít přímý nebo rozvětvený řetězec a zahrnují ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl a podobně.
-19Oxazinonové alkinylové skupiny, bu5 saaotné nebo s různýai výše uvedený»! substituenty, jsou nižší alkinylové skupiny, obsahující od dvou do šesti atoaů uhlíku v základní» řetězci a až 15 atoafi uhlíku· Mohou aít příaý nebo rozvětvený řetězec a zahrnují ethinyl, propinyl, butinyl, isobutinyl, aryl, hexinyl a podobné skupiny·
Příklady oxazinonových alkanoyloxyskupin zahrnují acetátovou, propionátovou, butyrátovou, valerétovou, isobutyrétovou skupinu a podobné skupiny. Kejpreferovanější skupinou je alkanoyloxyskupina.
^vedené oxazinonové arylové skupiny, buď saaotné nebo s rúznýai substituenty , obsahují od 6 do 15 atoaú uhlíku a zahrnují fenyl, ος -nafty1 nebo -naftyl atd. Substituenty zahrnují alkanoxyskupiny, hydroxyskupiny, halogen, alkylové skupiny, arylové skupiny, alkenylové skupiny, acylové skupiny, acyloxyskupiny, nitroskupiny, aeinoskupiny, axidoskupiny atd.. Nejpreferovanějšía arylea je fenyl.
vak je uvedeno výše aohou Rg a R^ oxazinonu vzorce 1 představovat-ΟΚθ, kde Rg je alkyl, acyl, ketal, ethoxyethyl (EE), 2,2,2-trichlorethoxyaethyl nebo jiná chránící skupiny hydroxylové skupiny jako acetalové a etherové, např. aethoxyaethyl (MOM), benzyloxyaethyl, esterové jako acetátová skupina, karbonátové skupiny jako je aethylkarbonát a podobně.Různé chránící skupiny hydroxylové skupiny a jejich syntéza aohou být nalezeny v Protective Groups in Organic Synthesís od T.W.Greenea, John Wiley and Soas, 1981. Chrá-20nící skupiny hydroxylové skupiny by měly být snadno odstranitelné za podmínek, které jsou dostatečně mírné a neporušují esterovou vazbu nebo jiné substituenty taxolových meziproduktů. Rg je výhodně ethoxyethyl nebo 2,2,2-trichlorethoxy methyl a nejvýhodněji ethoxyethyl.
Výhodné významy oxazinonových substituentů Rp > ^3» R^, Rg, R^ a Rg jsou uvedeny dále:
*·
-22Protože oxazinon vzorce I má několik asymetrických atomů uhlíku bud' odborníkům zřejmé, že sloučeniny podle předloženého vynálezu, sající asymetrické uhlíkové atoey nohou existovat v diastereoxerních, racesických nebo opticky aktivních formách. Všechny tyto formy jsou v souladu s nároky předloženého vynálezu, specifičtěji, předložený vynález zahrnuje enantiomery, diastereomer.y, raceaické směsi a jejich jiné směsi.
Oxazinony vzorce 1 mohou být připraveny ze snadno dostupných materiálů podle néáledujícíhb reakčního schématu:
^arboxylové kyselina vzorce 33 může být alternativně připravena postupem podle metody popsané Greenea a spol., JACS 110, 5917 (1988). p-laktatmy vzorce 32 aohou být připraveny ze snadno dostupných materiálů jak je uvedeno v následující» reakčnía schématu, kde Rj a Rj jsou fenyl, R^ a Rg jsou vodík a Sg je-ΟΗθ, kde Ηθ je ethoxyethyl:
činidla: a) triethylamin, CHgCD^ 25 °G, 18 h, b) 4 ekr. dusičnanu ceričito-amonného, CH^CN, -10 °G, 10 ain, c) KOH,
THF, H^O, 0 °C, 30 min, d) ethylvinylether, THF, toluensulfonové kyselina (kat.), 0 °C, 1,5 h, e) CH^Li, ether,. -78 °C, 10 ain, benzoylchlorid, -78 °G, 1 h.
-24Výchozí materiál je snadno dostupný. -Aeylpiyacetylchlorid se připraví Z glykolové kyseliny a za přítomnosti terciárního aminu kondenzuje za vzniku kruhu s iminem připravený» z aldehydu a p-methoxyanilinu za vzniku 1-p-methoxyfenyl-3-acyloxy-4-arylazetidin-2-onu.
p-Methoxyfenylová skupina aůže být snadno odstraněna oxidací dusičnane» ceričito-amonným a acyloxyskupiny může být hydrolyzována za standardních podmínek, které budou zřejmé odborníkům za vzniku 3-hydroxy-4-arylazetidin-2-onu.
3-Hydroxylové skupina může být chráněna různými obvyklými chránícími skupinami jako je 1-ethoxyethylová skupina. Výhodně se raceaický 3-hydroxy-4-arylazetidin-2-on rozštěpí ná čisté endntiomery před chráněním rekrystalizací příslušných 2-methoxy-2-(trifluormethyl$fenyloctových esterů a pro přípravu taxolu se použije pouze pravotočivý enantiomer. Popři pádě je možno 3-(1-ethoxyethoxy)-4-fenylazetid.in-2-on převeden na /^-laktam vzorce 32 zpracováním s bází, výhodně n-bu* tyllithiem a'aroylchloridem při teplotě —78 °C nebo nižší.
Následující příklady slouží k ilustraci vynálezu a nikterak jej neomezují.
Příklad 1
Příprava cis-2,4-difenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3oxazin-6-onu vzore cis-1-p-Methoxyfenyl-3-acetoxy-4-fenylazetidin-2-on.
K roztoku 962 mg (4,56 mmol) iminu odvozeného od benzaldehydu a p-methoxyanilinu a 0,85 ml (6,07 mmol) triethylaminu
-25v 15 ml CH2C12 při -20 °C se po kapkách přidá roztok 413 mg (3,04 mrnol) PQ-acetoxyacetylchloridu v 15 ml CH2C12· Reakční směs se nechá ohřát na 25 °C během 18 hodin· Reakční směs se pak zředí 100 ml CH2C12 a roztok se extrahuje 30 ml 10% vodné kyseliny chlorovodíkové. Organická vrstva se promyje 30 ml vody a 30 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným a zahuštěním se získá pevná hmota, '^ato pevná hmota se trituruje s 50 ml hexanu a směs se zfiltruje. Zbylá pevná látka se rekrystalizuje ze směsi ethylacetát/hexan, získá se 645 mg (68 %) cis1-p-methoxyfenyl-3-acetoxy-4-fenylazetidin~2-onu ve formě bílých krystalů, t.t. 163 °C.
cis-3-Acetoxy-4-fenylazetidin-2-on.
K roztoku 20,2 g cis-1-p-methoxyfenyl-3-acetoxy-4-fenylazetidin-2-onu v 700 ml acetonitrilu se při -10 °G pomalu přidá roztok dusičnanu ceričitoamonného ve 450 ml vody během 1 hodiny. Směs se míchá 30 minut při -10 °C a zředí se 500 ml etheru. Vodná vrstva se extrahuje dvěma 1 OOml dávka mi etheru a spojené vrstvy se promyjí dvěma 1OOml dávkami vody, dvěma 1OOml dávkami nasyceného hydrogensiřičitanu sodného, dvěma 1 OOml dávkami Nasyceného vodného hydrogenuhli— čítánu sodného a zahuštěním se získá 18,5 g pevné látky. Rekrystalizací pevné látky ze směsi aceton/hexan se získá
12,3 g (92 %) cis-3-acetoxy-4-fenylazetidin-2-onu jako bílých krystalů, t.t. 152 až 154 °C.
cis-3-%droxy-4-fenylazetidin-2-on.
Ke směsi 200 ml THF a 280 ml 1M vodného hydroxidu drasel
-26ného při 0 °0 se přidá roztok 4,59 g (22,4 mmol) cis-3-acetoxy-4-fenylazetidin-2-onu ve 265 ml THF pomocí přikapávací nálevky v průběhu 40 minut. Roztok se míchá při 0 °C po dobu 1 hodiny a přidá se 100 ml vody a 1 OOaml nasyceného hydrogenuhličitanu sodného. Směs se extrahqp čtyřmi podíly o objemu 200 ml ethylacetátu a spojeně organické vrstvy se suší nad síranem sodným a zahuštěním se získá 3,54 g (97 %) racemic— kého cis-3-hydroxy-4-fenylazetidin-2-onu ve formě bílých krystalů, t.t. 147 až 149 °C. Tento materiál se rozštěpí na své enantiomery rekrystalizaci jeho 2-methoxy-2-(trifluormethyl)— fenylesterů kyseliny octové ze směsi hexan/aceton s následující hydrolýzou / 77°.
cis-3-(1-Ethoxyethoxy)-4-fenylazetidin-2-on.
K roztoku 3,41 g (20,9 mmol) cis-3-hydroxy-4-fenylazetidin-2-onu v 15 ml THF při 0 °C se přidá 5 ml ethylvinyletheru a 20 mg (0,2 mmol) methansulfonové kyseliny. Směs se míchá při 0 °C po dobu 20 minut, zředí se 20 ml nasyceného hydrogenuhličitanu sodného a extrahuje se třikrát 40 ml dávkami ethylacetátu» Spojené ethylacetátové vrstvy se suší nad síranem sodným a zahuštěním se získá 4,87 g (99 %) cis-3-d-ethoxyethoxy )-4-fenylazetidin-2-onu ve formě bezbarvého oleje. cis-1-Benzoyl-3-(1-ethoxyethoxy)-4-fenylazetidin-2-on.
K roztoku 2,35 g (10 mmol) cis-3-(1-ethoxyethoxy)-4fenylazetidin-2-onu ve 40 ml THF se při -78 °C přidá 6,1 ml (10,07 mmol) 1,65M roztoku n-butyllithia v hexanu. Směs se míchá 10 minut při —78 °C a přidá se roztok 1,42 g (10,1 mmol) benzoylchloridu v 10 ml THF. Směs se míphá při -78 °G podobu 1 hodiny a zředí se 70 ml nasyceného vodného roztoku hydro-27genuhličitanu sodného a extrahuje se třikrát 5Oni dávkami ethylacetátu. Spojené ethylacetétové extrakty se suší nad síranem sodným a zahuštěním se získá 3,45 g ve formě oleje* Chromatografií oleje na silikagelu se elueí směsí ethylacetát /hexan získá 3,22 g (95 %) cis-1-benzoy1-3-(1-ethoxyethoxy)
4-fenylazetidin.-2-onu ve formě bezbarvého oleje. 2R,3S-N-Benzoyl-O-(1-ethoxyethyl)-3~fenylisoserin.
K roztoku 460 mg (1,36 mmol) cis-1-benzoy1-3-(1-ethoxyethoxy )-4*-fenylazetidin-2-onu ve 20 ml THF při 0 °G se přidá 13,5 ml 1M vodného roztoku (13,5 mmol) hydroxidu drasel- .
rt ného. Směs se míchá při 0 C po dobu 10 minut a THF se odpaří. Směs se rozdělí mezi 12 ml 1N vodného roztoku kyseliny chlorovodíkové a 30 ml chloroformu. Vodná vrstva se extrahuje dvakrát 30ml dávkami chloroformu. Spojené chloroformové extrakty se suší nad síranem sodným a zahuštěním se získá 416 mg (66 %) 2R,3S-N-benzoyl-0-(1-ethoxyethyl)-3-fenylisoserinu (vzorec 33, ve kterém a R^ jsou fenyl a ít, íe ethoxyethyl).
eis-2,4-Difenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin6-onu (vzorec ZJ).
K roztoku 416 mg (1,16 mmol) 2R,3S-N-benzoy1-0-(1-ethoxyethyl)-3-fenylisoserinu ve 20 ml THF se přidá 261 mg (2,33 mmol) pevného terc.butoxidu draselného a směs se míchá při 25 °G po dobu 30 minut. Roztok 134 mg (1,16 mmol) methansulfonylchloridu ve 3,2 ml THF se přidá k této směsi a míchá se při 25 °C po dobu 1,5 hodiny. Směs se zředí 80 ml hexanu a ethylacetátu a tento roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného a 10 ml solanky. Orga-28nická fáze se suší nad síranem sodným a zahuštěním se získá
256 mg (65 %) cis-2,4-difeny1-5-(1-ethoxyethoxy)-4,5-dihydro1,3-oxazin-6-onu vzorce II jako bezbarvého oleje, /0(/2^ «
Hg
-22° (CHClp c= 1,55).
Příklad 2
Příprava taxolu
Do malé reakční baňky se vloží 77 mg (0,218 mmol) (-Jc is-2,4-dif eny1-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin6-onu (vzorec II), 4θ mg (0,057 mmol) 7-O-triethylsilylbakatinu vzorce III, 6,9 mg (0,057 mmol) 4-dimethylaminopyridinu (DMAP) a 0,029 ml pyridinu, Směs se míchá při 25 °C po dobu 12 h a zředí se 100 ml ethylacetátu. ^thylacetétový roztok se extrahuje 20 ml 10% vodného roztoku síranu měďnatého, suší se nad síranem sodným a zahustí, ^bytek se filtruje přes sloupečel silikagelu a eluuje ethylacetétem. Rychlou chromatograf i í na silikagelu a elucí směsí ethylacetát/hexan s následující rekrystáližací ze.směsi ethylacetát/hexan se získá 46 mg (77 %) 2*~O*(1-ethoxyethyl)-7-0-triethylsilyltaxolu jako zhruba 2:1 směsi diastereomerů a 9,3 mg (23 %) 7-O-triethylsilylbakatinu vzorce III. Výtěžek vztažený na spotřebovaný 7-0-triethylsilylbakatin vzorce III je kvantitativní.
mg vzorku 2*-(1-ethoxyethyl)-7-0-triethylsilyltaxolu se rozpustí ve 2 ml ethanolu a přidá se 0,5 mů 0,5% roztoku vodné kyseliny chlorovodíkové. Směs se míchá při 0 °G po dobu 30 h a zředí se 50 ml ethylacetátu, Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného*
29suší se nad síranem sodným a zahustí. Zbytek se čistí sloup covou chromatografií na silikagelu za eluce směsí ethylace tát/hexan, získá se tak 3,8 mg (cca 90 %) taxolu, který je identický s autentickým vzorkem ve všech ohledech.
Příklad 2
Příprava N-debenzoyl-N-terc.butoxyk.arbonyltaxolu
2.Pere.butoxy-4-fenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3óxazin-6-on.
K roztoku 409 mg (1,16 mmol) N-terc.butoxykarbony1-0-30(1-ethoxyethyl)-3-fenylisoserinu (3) ve 20 ml THF se přidá 261 mg (2,33 mmol) pevného terc.butoxidu draselného a směs se míchá při 25 °G po dobu 30 minut, ^řidá se roztok 134 mg (1,16 mmol) methansulfonylchloridu ve 3,2 ml THF a směs i
se míchá při 25 °G po dobu 1,5 hodiny. Směs se zředí 80 ml hexanu a ethylacetátu a tento roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného a 10 ml solanky. Organická fáze se suší nad síranem sodným, zahuštěním se získá 235 mg (70 %) 2-terc.butoxy-4-feny1-5-(1-ethoxyethoxy )-4,5-dihydro-1 ,3-oxazin-6-onu jako bezbarvého oleje.
N—Jebenzoyl-N-terc.butoxykarbonyltaxol.
v
Do malé reakční banky se vloží 73 mg (0,218 mmol) 2-terdbutoxy-4-feny1-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6onu, 40 mg (0,057 mmol) 7-O-triethylsilylbakatinu III, 6,9 mg (0,057 mmol) 4-dimethylaminopyridinu (DMAP) a 0,029 ml pyridinu. Směs se míchá při 25 °C po dobu 12 hodin a zředí se 100 ml ethylacetátu. ^thylacetátový roztok se extrahuje 20 ml 10% vodného roztoku síranu mělnatého, suší se nad síranem sodným a zahustí. Zbytek se zfiltruje přes krátký sloupec silikagelu za eluce ethylacetétem. Rychlou chromatografií na silikagelu za eluce směsí ethylacetát/hexan s následující rekrys talizací se získá ze směsi ethylacetát/hexan 44 mg (73 %) N-debenzoyl-N-terc.butoxykarbonyl-2*- (1-ethoxyethoxy)-7-0triethylsilyltaxolu jako cca 1:1 směsi distereomerů a 9,3 Mg (23 %) 7-0-triethylsilylbakatinu III.
-315 mg vzorku N-debenzoyl-N-terc.butoxykarbonyl-2*-(1ethoxyethoxy)-7-*0-triethylsilyltaxolu se rozpustí ve 2 ml ethanolu a přidá se 0,5 ml 0,5% vodného roztoku kyseliny chlorovodíkové. Směs se míchá při 0 °C po 30 hodin a zředí, se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší nad síranem sodným a zahustí. Zbytek se čistí sloupcovou chromatografií na silikagelu za eluce směsí ethvlacetát/hexan, získá se 3,8 mg (cca 90 %) N-flebenzoyl-N-terc. butoxykarbonyltaxolu.
Příklad 4
Příprava N-debenzoyl-N-terc.butoxykarbonyl-2(1-ethoxyethyl )-3 *-fenyltaxolu tBuO,
OEE
co2h tBuC^^xO
T v
0 '^OEE
2-terč.Butoxy-4,4-difenyl-5-(1-ethoxyethoxy)-4,5-dihydro1 ,3-oxazin-6-on.
K roztoku 497 mg (1,16 mmol) N-terc.but.oxykarbonyl-0(1-ethoxyethyl)-3,3-difenylisoserinu (3) ve 20 ml THF se přidá 261 mg (2,33 mmol) pevného terc.butoxidu draselného a směs se míchá při 25 °G po dobu 30 minut. Přidá se roztok134 mg (1,16 mmol) methansulfonylchloridu ve 3,2 ml THF a směs se míchá při 25 °G po 1,5 hodiny. Směs se zředí 80 ml hexanu a ethylacetátu a tento roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného a 10 ml solanky. Organická fáze se suší nad síranem sodným a zahustí se, získá se 243 mg (59 %) 2-terc.butoxy-4,4-difenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin6-onu jako bezbarvého oleje.
N-Debenzoyl-N-terc.butoxykarbonyl-3 ^-fenyltaxol.
Do malé reakční nádoby se vloží 90 mg (0,218 mmol)
2-terc.butoxy-4,4-difeny1-5-(1-ethoxyethoxy) -4,5-dihydrot ,3-oxazin-6-onu, 40 mg (0,057 mmol) 7-O-triethylsilylbakatinu III, 6,9 mg (0,057 mmol). 4-dimethylaminopyridinu (DMA?) a 0,029 ml pyridinu. Směs se míchá při 25 °C po dobu 12
-33hodin a zředí se 100 ml ethylacetátu. Ethylacetátový roztok se extrahuje 20 ml 10% vodného roztoku síranu měánatého, suší nad síranem sodným a zahustí, ^bytek se v ethylacetátu přefiltruje přes krátký sloupec silikagelu. Rychlou chromatografií na silikagelu za eluce směsí ethylacetát/ hexan s následující rekrystalizací ze směsi ethylacetát/ hexan se získá 44 mg (66 %) N-debenzoyl-N-terčobutoxykarbony 1-2z-(1-ethoxyethyl)-3 *-feny1-7-0-tri ethyls ilyltaxolu jako cca 3:1 směsi diastereomerů.
mg vzorku N-debenzoyl-N-terc.butoxykarbony1-2 (1-ethoxyethyl)-3*-fenyl-7-0-triethylsilyltaxolu se rozpustí ve 2 ml ethanolu a přidá se 0,5 ml 0,5% vodného roztoku HGl. Směs se míchá při 0 °G po 30 minut a zředí se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným a zahustí, úbytek se čistí, sloupcovou chromatografií na silikagelu za eluce směsí ethylacetát/hexan, získá se 4,0 mg (cca 90 %) N-debenzoyl-N-terc.butoxykarbonyl-3 *-fenyltaxolu.
Příklad 5 ^Příprava 2,4-difeny1-5-(1-ethoxyethoxy)-5-methy1-4,5dihydro-1,3-oxazin-6-onu
roztoku 430 mg (1,16 mmol) N-benzoyl-0-(1-ethoxyethyl )-2-methyl-3-fenylisoserinu ve 20 ml THF se přidá 261 mg (2,33 mmol) pevného terc.butoxidu draselného a směs se míchá při 25 °C po dobu 30 minut. Přidá se roztok 134 mg (1,16 mmol) methansulfonylchloridu ve 3,2 ml THF a směs se míchá při 25 °C po dobu 1,5 hodiny. Směs se zředí 80 ml hexanu a ethylacetétu a tento roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného a 10 ml solanky. Organická fáze se suší nad síranem sodným a zahuštěním se získá 270 mg (76 %) 2,4-difenyl5-(1-ethoxyethoxy)-5-methy1-4,5-dihydro-1,3-oxazin-6-onu jako bezbarvého oleje.
-35Příklad 6 *-Methyltaxol
Do malé reakční baňky se vloží 77 mg (0,218 mmol)
2,4-d ifenyl-5-(1-ethoxyethoxy)-5-methy1-4,5-dihydto-1,3oxazin-6-onu, 40 mg (0,057 mmol) 7-O-triethylsilylbakatinu III, 6,9 mg (0,057 mmol) 4-dimethylaminopyridinu (DMAP), a 0,029 ml pyridinu. Směs se míchá při 25 °C po dobu 12 hodin a zředí se 100 ml ethylacetátu. Ethylacetátový roztok se extrahuje 20 ml 10% vodného roztoku síranu měánatého, suší se nad síranem sodným a zahustí. Zbytek se přelije přes krátký sloupec silikagelu za eluce ethylacetátem. Rychlou chromatografií na silikagelu za eluce směsí ethylacetát/hexan s následující rekrystalizací ze směsi ethylacetát/hexan se získá 32 mg (53 %) 2(t-ethoxy-ethyl)-3*methyl-7-0-triethylsilyltaxolú jako směsi cca 1:1 diastereomerů.
mg 2*-(1-ethoxyethyl)-3*-methyl-7-O-triethylsilyltaxolu se rozpustí ve 2 ml ethanolu a přidá’ se 0,5 ml 0,5% vodného roztoku kyseliny chlorovodíkové. Směs se míchá při 0 °C po 30 hodin a zředí se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným a zahustí. Zbytek se čistí sloupcovou chromatografií na silikagelu za elu4 ce směsí ethylacetát/hexan, získá se 3,9 mg (cca 90 %) 3*methy1taxolu.
vloží 125 mg /0,320 mrnol/
Příklad 7
N-Lebenzoyl-N-/1-naftoyl/taxol
Do malé reakční nádoby se
2-/1-naftyl/-4-fenyl-5-/1-ethoxyethoxy/-4,5-dihydro-1, 3oxazin-6-on, 45 mg /0,064 mrnol/ 7-0-triethylsilyl-bákatinu III, 7,8 mg /0,064 mrnol/ 4-dimethylaminopyridinu /DMAP/ a 0,32 ml pyridinu. Směs se míchá při 25 °C 12 hodin a zředí se 100 ml ethylacetátu. Ethylacetátový roztok se extrahuje 20 ml 10% vodného roztoku síranu mědnatého, suší se nad síranem sodným a zahustí. Zbytek se zfiltruje přes sloupeček silikagelu, eluuje se ethylacetátem. Rychlou chromatografií na silikagelu se pak eluuje směsí ethylacetát/hexan a rekrystaluje ze směsi ethylacetát/hexan, získá se 62 mg /90 %/ N-debenzoyl-N-/1-naftoyl/-2*-/lethoxyethoxy/-7-O-triethylsilyltaxolu.
mg vzorek N-debenzcyl-N-/i-nafto.yl/-2*-/l-ethoxyethoxy/-7-O-triethylsilyltaxolu se rozpustí ve 2 ml ethyn nolu a přidá se 0,5 ml 0,5% vodného roztoku HCl. Směs se míchá při 0 °C 30 hodin a zředí se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným a zahustí. Zbytek se čistí sloupcovou chromatografií na silikagelu, eluuje ethylacetátem/hexanem, získá se 3,9 mg /asi 95 %/ N-dehenzoyl-N-/l-naftoyl/taxolu.
Příklad 8
N-Debenzo.yl-N-/2-naf toyl/taxol
Do malé reskční nádoby se vloží 125 mg /0,320 mrnol/
2-/2-naftyl/-4-fenyl-5-/l-ethoxyethoxy/-4,5-dihydro-1,3oxazin-6-onu, 45 mg /0,064 mrnol/ 7-C-trietnylsilyl-bakatinu III, 7,8 mg /0,064 mrnol/ 4-dimethylaminopyridinu /DMAP/ a 0,32 ml pyridinu. Směs se míchá při 25 °C 12 hodin a zředí se 100 φΐ ethylacetátu. Ethylacetátový roztok se extrahuje 20 ml 10% vodného roztoku síranu mědnatého, suší se nad síranem sodným a zahustí. Zbytek se filtruje přes slou-37peček silikagelu, eluuje ethylacetátem. Rychlou chromatografií na silikagelu za eluce ethylacetátem/hexanem a rekrys táli žací z ethylacetátu/hexanu se získá 64 mg /93 %/ N-debenzo.yl-N-/2-naf toyl/-2 *-/1 -ethoxyethoxy/-7-0-triethylsilyltaxol.
mg vzorek N-debenzoyl-N-/2-naftoyl/-2*-/1-ethoxyethoxy/-7-0-triethylsilyltaxolu se rozpustí ve 2 ml ethanolu a přidá se 0,5 ml 0,5% vodného roztoku HC1. Směs se míchá při 0 °C po 30 h a zředí se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného roztoku hydrogenuhličitanu sodného /vodný/, suší nad síranem sodným a zahustí. Zbytek se čistí sloupcovou chromatografií na silikagelu, eluuje ethylacetétem/hexanem, získá se 3,5 g /cca 90 %/ N-debenzoyl-N-/2-naftoyl/-taxolu.
Příklad 9
N-Bebenzoyl-N-pivaloyl-taxol
Do malé reakční nádoby se vloží 102 mg /0,320 mmol/
2-terc.butyl-4-feny1-5-/1-ethoxyethoxy/-4,5-dihydro-1 ,3oxazin-6-onu, 45 mg /0,064 mmol/ 7-O-triethylsilyl-bakatinu III, 7,8 mg /0,064 mmol/ 4-dimethylaminopyridinu /DMAP/ a 0,032 ml pyridinu. Směs se míchá při 25 °C po 12 h a zředí se 100 ml ethylacetátu. Ethylacetátový roztok se extrahuje 20 ml 10% vodného roztoku síranu měďnatého, suší nad síranem sodným a zahustí. Zbytek se filtruje přes sloupeček silikagelu, eluuje ethylacetátem. Rychlou chromatografií na silikagelu za eluce ethylacetátem/hexanem s následující rekrystalizací z ethylacetátu/hexanu se získá 55 mg /85 %/ N-debenzo.yl-N-pivaloyl-2*-/l-ethoxyethoxy/-7-0triethylsilyl-taxolu.
-385 mg vzorek N-debenzo.vl-N-pivaIovl-2 *-/1 -ethoxyethoxy/7-O-triethylsilyltaxolu se rozpustí ve 2 ml ethanolu s přidá se 0,5 ml 0,5% vodného roztoku HC1. Směs se míchá při θ °C po 3 hodiny a zředí se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným a zahustí, úbytek se čistí sloupcovou chromatografií na silikagelu za eluce ethylacetátem/hexanem, získá se 3,6 mg /cca 52 %/ N-debenzoyl-N-pivaloyltaxolu.
Příklad 10
N-Debenzo.yl-N-pentanoyl-taxol ho malé reakční nádoby se vloží 102 mg /0,320 mmol/ 2-n-butyl-4-fenyl-5-/1-ethoxyethoxy/-4,5-dihydro-1,3-οχθζίη6- onu, 45 mg /0,064 mmol/ 7-O-triethylsilyl-bakatinu III,
7,8 mg /0,064 mmol/ 4-dimethylaminopyridinu /Ώ1ΛΡ/ a 0,032 ml pyridinu. Směs se míchá při 25 po 1 hodinu a zředí se 100 ml ethylacetátu. Ethylacetátovy roztek se extrahuje 20 ml 10% vodného roztoku síranu mědnatého, suší se nad síranem sodným a zahustí. Ebytek se filtruje přes sloupeček silikagelu, eluuje ethvlacetátem. Rychlou chromatografií na silikagelu za eluce ethylacetátem/hexanem s následující rekrystalizací ze směsi ethylacetát/hexan se získá 58 mg /89 %/ N-debenzoyl-N-pentanol-2*-/ 1-ethoxyethox,y/-7-0-trieth.yls i lvi taxolu.
mg vzorek K-debenzoyl-K-pentano^l-2 -/1-ethoxyethoxy/7- ú-trimethylsil.yl-taxolu se rozpustí ve 2 ml ethanolu a přidá se 0,5 ml 0,5% vodného roztoku HC1. Směs se míchá při O °C 30 h a zředí se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným s zahustí. Zbytek se čistí sloupcovou chromatografií na silikagelu za eluce ethylacetátem/hexanem, získá se 3,6 mg /asi 52 %/ N-debenzoyl
-39K-pentano vl -texolu.
Příklad 11 ’-Zesfenyl-3 *-/1 -naftyl/-taxo1
3o malé reakční nádoby se vloží 125 mg /0,320 mmol/
2-fenyl-4-/1-naftvl/-5-/1-ethoxyethox.y/-4,5-cihydro-1,3oxazin-6-onu, 45 mg /0,064 mmol/ 7-O-triethylsilvlbakatinu III, 7,8 mg /0,064 mmol/ 4-dimethylaminopyridinu /DMA?/ a 0,032 ml pyridinu- Směs se míchá při 25 °0 po 12 hodin s zředí se 100 ml ethylacetátu. Ethylacetátovy roztok se extrahuje 20 ml 10% vodného roztoku sírahu mědnatého, /
suší se nad síranem sodným a zahustí. Zbytek se filtruje přes sloupeček silikagelu za eluce ethylacetatem. Rychlou chromatografií na silikagelu za eluce ethylacetátem/hexanem s následující rekrystáližací z ethylacetátu/hexanu se získají 62 mg /90 %/ 2*-/1-ethoxyethoxy/-3'-česfenyl3 *-/1-naftyl/-7-O-triethyltaxolu.
mg vzorek 2*-/1-ethoxyethoxy/-3*-desíenyl-3*-/lnaftyl/-7-Z-triethylsilyltaxolu se rozpustí ve 2 ml ethanolu a přidá se 0,5 ml 0,5% vodného roztoku HC1. Směs se míchá při 0 °C po 30 h a zředí se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným a zahustí se. Zbytek se čistí sloupcovou chromatografií na silikagelu za eluce ethylacetátem/hexanem, získá se 3,9 mg /as: 95 %/ 3 z-desfenyl-3 *-/l-naf t.yl/t i xolu.
Příklad 12 *-desfenyl-3*-/2-naftyl/taxol
Do malé reakční nádoby se vloží 125 mg /0,320 mmol/ 2-fen,yl-4-/2-na tyl/-5-/l -ethoxyethoxy/-4,5-dihydro-1 , 3oxazin-ó-onu, 45 mg /0,064 mmol/ 7-0-trieth Isilylbakatinu III, 7,8 mg /0,064 mmol/ 4-dimethylaminopyridinu /DMAP/ a
-40ε 0,032 ml pyridinu. Směs se míchá při 25 °C po 12 h a zředí se 100 ml ethylacetátu. Ethylscetátový roztok se extrahuje 20 ml 10% vodného roztoku síranu mědnatého, suší se nad síranem sodným s zahustí. Zbytek se zfiltruje pres sloupeček silikagelu, eluuje ethylacetátem. -vchlou chromatografií na silikagelu za eluce ethylscetátem/hexanem s následující rekrystalizací z ethylacetátu/hexanu se získá ji 62 mg /90 %/ 2*-/1-ethoxyethoxy/-3*-desfenyl-j*-/2naftyl/-7-0-triethylsilyltaxolu.
mg vzorek 2*-/l-ethoxyethoxy/-3*-*desf enyl-3 *-/2naftyl/-7-O-triethylsilyltaxol se rozpustí ve 2 ml ethanolu a přidá se 0,5 ml 0,5% vodného roztoku KC1. Směs se míchá při 0 °C po 30 h a zředí se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným a zahustí, “bytek se čistí sloupcovou chromatografií na silikagelu za eluce ethylacetátem/hexanem, získá se 3,9 mg /asi 95 %/ *-de síenyl- 3 *-/2-n aí tyl/r axolu.
Příklad 13 z-desf enyl-3 *-terc . but.yltaxol
Po malé reakční nádoby se vloží 102 mg /0,320 mmol/
2-fenyl-4-terc.butyl-5-/l-ethoxyethoxy/-4,5-dihydro-1,3oxazin-6-onu, 45 mg /0,064 mmol/ 7-O-triethvlsilylbakatinu III, 7,8 mg /0,064 mmol/ 4-dimethvlasinopyridinu /DMA?/ a 0,032 ml pyridinu. Směs se míchá při 25 °C 12 h a zředí se 100 ml ethylacetátu. Ethylacetátový roztok se extrahuje 20 ml 10% vodného roztoku síranu mědnatého, suší se nad síranem sodným a zahustí- Zbytek se zfiltruje přes sloupeček silikagelu a eluuje ethylacetátem. Rychlou chromatografií na silikagelu za eluce ethylacetátem/nexanem s následující rekrystalizací z ethylacetátu/hexanu se získá 5θ mg /89 %/ 2*-/1-ethoxyethoxy/-3- desfenyl-3'-terč.buty1-7-0 triethylsilyltaxolu.
-415 mg vzorku 2<'-/1-ethoxyethoxy/-J*-desřenyl-5z-terc. butyl-7-O-triethylsilyltaxolu se rozpustí ve 2 ml ethanolu s přidá se k němu 0,5 ml 0,5% vodného roztoku HC1. Směs se míchá při 0 °C po j hodiny a zředí se 50 ml ethylacetétu Rožtok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným a zahustí. Zybtek se čistí sloupcovou chromatografií na silikagelu za eluce ethylacetátem/hexanem, získá se 3,6 mg /asi 92 %/ 3*-desfenyl-3*-terc.butyltaxolu.
Příklad 14
3*-desfenyi-3*-p-methoxyfenyltaxol
Do malé reakční nádoby se vloží 118 mg /0,320 mmol/ 2-fenyl-4-p-methoxyfenyl-5-/1-ethoxyethoxy/-4,5-dihydro1,3-oxazin-6-onu, 45 mg /0,064 mmol/ 7-0-triethylsilylbakatinu III, 7,8 mg /0,064 mmol/ 4-dimethvlaminopyridinu /DMPá/ a 0,032 ml pyridinu. Směs se míchá při 25 °0 po 12 hodin a zředí se ICO ml ethylacetátu- Ethylacetátovy roztok se extrahuje 20 ml 10% vodného roztoku síranu měčnatého, suší se nad síranem sodným a zahustí. Zbytek se filtruje pres sloupeček silikagelu za eluce ethylacetátem. Rychlou chromatografií na silikagelu za eluce ethylacetátem/hexanem s následující rekrystalizací z ethylácetátu/hexanu se získá 58 mg /87 %/2*-/1-ethoxyethoxy/-3*-desfenyl3 *-p-methoxyfenyl-7-0-triethylsilyltaxolu.
mg vzorek 2*-/1-ethoxyethoxyz'-3*-desfenyl-3*-pmethoxyf enyl-7-O-triethyl-sil.yltaxolu se rozpustí ve 2 ml ethanolu a přidá se 0,5 ml 0,5% vodného roztoku HC1. Směs se míchá oři 0 °C 30 hodin a zředí se 50 mi ethylacetétu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hvcrogenuhličitanu sodného, suší se nad síranem sodným a zahustí. Zbytek se čistí sloupcovou chromatografií na silikagelu s elucí ethylacetátem/hexanem, získá se 3,6 mg /asi 90 %/ 3*-óesfenyl-3*-ú-methoxyfenyltaxolu.
-42Příklad 15
N-debenzoyl-N-/2-naf toyl/-3*-desfenv 1-3 *-/1 -nafty 1/taxol
Do malé reakční nádoby se vloží 140 mg /0,320 mmol/ 2-/2-naftyl/-4-/l -naf tyl/-5-/l -ethoxyethoxy/-4,5-dih,ydro1,3-oxezin-6-onu, 45 mg /0,064 mmol/ 7-J-triethylsilylbakatinu III, 7,8 mg /0,064 mmol/ 4-čimethylaminopyridinu /DMAP/ a 0,032 ml pyridinu. Směs se míchá při 25 °C 12 hodin, a zředí se 100 ml ethylacetátu» Ethylacetátovy roztok se extrahuje 20 ml 10% vodného roztoku síranu měSnatého, suší se nad síranem sodným a zahustí. Zbytek se zfiltruje přes sloupeček silikagelu a eluuje ethylacetátem Rychlou chromatografií na silikagelu za eluce ethylacetátem/hexanem s následující rekrystalizací z ethylacetátu/ hexanu se získá 51 mg /70 %/ N-debenzoyl-N-/2-naftoyl/2*-/l -ethoxyethoxy/-3^-desf enyl-3 ''-/I -naf tyl/-7-0-triethyl silyltaxolu.
mg vzorek N-debenzoyl-N-/2-nafto,yl/-2*-/1-ethoxyethox,y/-3*-desf enyl-3-/1 -naf tvl/-7-°- triethylsilyltaxolu se rozpustí ve 2 ml ethanolu a přidá se 0,5 ml 0,5% vodného roztoku HC1. Směs se míchá při 0 °C po 30 h a zředí se 50 ml ethylacetátu. Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad sí raném sodným a zahustí- Zbytek se čistí sloupcovou chromatografií na silikagelu za eluce ethvlacetátem/hexanem, získá se 3,3 mg /asi 80 %/ N-debenzo,yl-N-/2-naf toyl/-3*desfenyl-3*-/1-naftyl/taxolu.
Příklad 16
N-debenzoyl-N-terc.butoxykarbonyl-10-deacetyltaxol /Taxotere/
Do malé reakční nádoby se vloží 73 mg /0,218 mg/ 2-terc. butox.y-4-fenyl-5-/1-ethoxyethoxy/-4,5-dihydro-1 ,3oxazin-6-onu, 44 mg /0,057 mmol/ 7,1O-bis-O-triethylsilyl-43bakatinu III, 6,5 mg /0,057 mmol/ 4-dimethylaminop.vridinu /DMAP/ s 0,029 ml pyridinu. Směs se míchá pri 25 °9 po 12 hodin a zředí se 100 ml ethylacetátu. Ethylscetátovy roztok se extrahuje 20 ml 10% vodného roztoku síranu měSnatého, suší nad síranem sodným a zahustí. Zbytek se filtruje přes s oupeček silikagelu za eluce eth.ylacetétem. Rychlou chromatografií na silikagelu za eluce ethylacetátem/hexanem s následující rekrystalizací z ethylacetátu/hexanu se získá 45 mg /68 %/ N-debenzoyl-N-terc.butokykarbonyl-2*/1-ethoxyethoxy/-7,1Q-bis-O-triethylsilyltaxolu jako směsi diastereomerů 1:1.
mg vzorku N-debenzovl-N-terc.butoxykarbonyl-2*/1-ethoxyethoxy/-?,1O-bis-O-triethylsilyltaxolu se rozpustí ve 2 ml ethanolu a přidá se 0,5 ml 0,5% vodného rozteku HC1. Směs se míchá při 0 °C a zředí se 50 ml ethylacetátu- Roztok se extrahuje 20 ml nasyceného vodného roztoku hydrogenuhličitanu sodného, suší se nad síranem sodným a zahustí. Zbytek se čistí sloupcovou chromatografií na silikagelu za eluce ethylacetátem/hexanem, získá se 3,S mg /asi 90 %/ N-debenzovl-N-terč.butoxykarbonyl-10-deacetyltaxolu.
uvedený popis je nutno chápat jako ilustrativní, nebol je mož o provést různé změny aniž by došlo k vybočení z rozsahu vynálezu. Popisem ani příklady není předmět vynálezu nikterak omezován.
Technical field
The invention relates to a process for the preparation of taxol with anticancer activity and oxazinone as an intermediate for this preparation.
Background Art
Taxanes are a group of terpenes that pay close attention to both biologists and chemists. Taxol, a member of this group, is a promising cancer chemotherapeutic agent with a broad spectrum of anti-cecas-γ,,. ,, leukemic and inhibiting activities. Taxol has the following structural formula:
Due to this promising activity, taxol clinical trials are conducted in both France and the United States.
Currently, taxol is obtained from the bark of several yew species for these clinical trials. However, taxol is present only in small amounts in the bark of these slowly growing, evergreen trees. This raises considerable concerns that these limited taxol stocks will not be sufficient to meet the requirements. Therefore, in recent years, chemists have been trying to develop an acceptable method for preparing taxol. So far, the results have not been fully satisfactory.
One of the synthetic pathways proposed has been the synthesis of the t-acyclic taxane nucleus from commercially available chemicals. Taxufin-related taxol synthesis has been described by Holton et al., JAGS. 110, 6558 (1988). Despite the progress this process has made, the ultimate complete synthesis of taxol is eefeo, probably a multi-stage, lengthy and costly procedure.
An alternative procedure for preparing taxol has been described by Greeneis et al., JACS 110, 5917 (1988). This procedure uses 1-O-deacetyl-baccatin III related to the taxol of the following formula:
10-Deacetyl bakatin III is more readily available than taxol since it can be obtained from Taxus baccata leaves. By the method of Greene et al., 10-deacetyl-bakatin III is converted to taxol by attaching an acetyl group to a carbon atom and attaching the ω-amido ester side chain to the carbon atom by esterifying the alcohol at the carbon atom with a ((amid-amidocarboxylic acid). requires rela
Only a few degrees, the synthesis of the fb-amidocarboxylic moiety is a multi-step process that proceeds with low yield. the condensation reaction is lengthy and also low in yield. However, the condensation reaction is a key step in the synthesis required for each contemplated synthesis of taxol or biologically active taxol derivative, as Wani et al., JACS 93,2325 (1971) has shown that the addition of a 5-amidoester side chain A chain of carbon is needed for antitumor activity.
The main problem in the synthesis / axol and other potential of their antitumor agents is the lack of readily available units / parts that would readily attach to the oxygen on the atom to form the β-amido ester side chain. The development of such a unit and the method of linking it in a high yield would facilitate the synthesis of taxol and similar antitumor agents having a modified series of substituents on the nucleus or a deleted side chain at the Cjj atom. This need is fulfilled by the discovery of a new, readily available chemical unit of the side chain precursor and an efficient way of linking it to an oxygen atom at the C atom.
SUMMARY OF THE INVENTION It is an object of the present invention to provide a side chain precursor for the synthesis of taxols and to provide a process for attaching a side chain precursor in a relatively high yield to yield the taxol intermediate.
3a
SUMMARY OF THE INVENTION
in which it is
R 1 is phenyl, x- or p-naphthyl, C 1-6 alkyl or t-butoxy,
R 2 is phenyl, c- or p-naphthyl, C 1-6 alkyl or p-met boxes of phenylene,
Ph phenyl,
Ac acetyl according to the invention is characterized in that the oxazinone of the general formula I is present
TX Ν '^ Λ θΠ.
(I) wherein R 1 and R 2 are as defined above, and wherein R 3 is a hydroxy protecting group, contacting an alcohol of formula III
HOlIltl
(III) wherein Ph and Ac are as defined above, in the presence of an activating agent, and the resulting β-amidoester is hydrolyzed.
The subject of the invention is also a precursor of the sidebar, an intermediate for the preparation of taxol, the oxazinone of the formula I
wherein R 1 is aryl, heteroaryl, alkyl, alkenyl, alkynyl, or OH 2 wherein Ηγ is alkyl, alkenyl, alkynyl, aryl or heteroaryl, B 8 and R 8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and -ΟΒΟΒ where Rg is alkyl, alkenyl, alkynyl, aryl, heteroaryl or a hydroxyl protecting group, and R 1 and R 8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl ·
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The method of preparing taxol products which is characterized by contacting an alcohol with an oxazinonene of formula I in the presence of a sufficient amount of activating agent to cause the reaction of oxaztone with an alcohol to form a β-amido ester which can be used as intermediate in taxol synthesis.
• -5 balsa objects vlastnooti present invention further illustrates j 1 1 following description.
The present invention relates to oxazinone of formula I and derivatives thereof.
(AND)
In said formula, as defined above, E 1 is aryl, heteroaryl, alkyl, alkenyl, alkynyl or -OR 1, where Βγ is alkyl, alkenyl, alkynyl, aryl or heteroaryl, Eg and are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and -ΟΒΟΒ where Βθ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxyl protecting group, and B y and R g are independently selected from the group consisting of hydrogen, alkyl, alkenyl alkynyl, aryl and heteroaryl.
Preferably, the oxazinone of formula I is of formula IA
(IA) «3
Where Rj, Hj and Βθ are as defined above, and preferably, Rg is ethoxyethyl or 2,2,2-trichloroethoxymethyl. Formula nejvýhodnějáího oxazinone in which »R i and R j 60U phenyl, R₁ is hydrogen and R2 is" org where Bg is longer ethoxyethyl is shown:
Ph "3 5 4> a
About 5 '\ t
OEE
Ph
In accordance with IUPAC rules, the name oxazinone of formula II is 2,4-diphenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazine-6-one.
According to the present invention, taxol intermediates, natural taxol and non-naturally occurring taxols having the following formula are prepared:
-7kde
A and B are each independently hydrogen or lower alkanoyloxy, alkenyloxy, alkyloxy or aryloyloxy or
A and B together form an oxo group,
L and D are each independently hydrogen or hydroxyl or lower alkanoyloxy, alkenoyloxy, alkyloxy or aryloyloxy,
E and F independently of one another are hydrogen or lower alkylamino, alkenyloxy, alkyloxy or aryloyloxy, or
E and F together form an oxo group,
G is hydrogen or hydroxyl or lower alkanoyloxy, alkenoyloxy, alkyloxy or aryloyloxy, or
G and I c together form an oxo group or a methylene group or
G and II together form an oxirane ring or
M and F together form an oxetan ring,
J is hydrogen, hydroxy or lower alkanoyloxy, alkenoyloxy, alkynyloxy, or arylcyloxy or
I is hydrogen, hydroxy or lower alkanoyl, alkenoyloxy, alkynyloxy or aryloxy, e.g.
I and J together form an oxo group and
K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynyloxy or aryloyloxy;
P and independently of one another are hydrogen or a lower alkanoyl-oxy group, an alkenoyloxy group, an alkyloxy group or an aryloyloxy group, or
P and Q together form an oxo group and
S and T independently represent hydrogen or lower alkanoyloxy, alkenoyloxy, alkynyloxy or aryloyloxy, or
S and T together form an oxo group and
U and V independently represent hydrogen or lower alkyl, alkenyl, alkynyl, aryl, or substituted aryl and
W is aryl, substituted aryl, lower alkyl, alkenyl, alkynyl, alkoxy or aryloxy.
laxol alkyl groups, either alone or with different substituents as defined above, preferably represent lower alkyl containing from one to six carbon atoms in the base chain and up to 10 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl. , butyl, isobutyl, tert-butyl, aryl, hexyl and the like.
The xxologic alkenyl groups, either alone or with different substituents as defined above, are preferably lower alkenyl containing preferably from two to six carbon atoms in the backbone and up to 10 carbon atoms. They may be straight-chain or branched and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl and the like.
Taxol alkynyl groups, either alone or with various substituents defined above, preferably represent lower alkynyl, containing from two to six carbon atoms in the backbone and up to 10 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutinyl, aryl, hexynyl and the like.
Examples of the alkanoyloxy group include acetate, propionate, butyretic, valerate, isobutyrate, and the like. The most preferred alkanoyloxy group is the acetic group.
Taxol aryl groups, either alone or with different substituents, contain from 6 to 10 carbon atoms and include phenyl, -naphthyl or fb-naphthyl, etc. Substituents include alkanoyl, hydroxy, halogen, alkyl, aryl, alkenyl, acyl , acyloxy, nitro, amino, amido, etc. The most preferred aryl is phenyl.
As defined above, the term aryloyloxy "includes aromatic heterocyclic groups, the term aryl" includes any compound having an aromatic ring that does not contain a heteroatom and the term heteroaryl includes any compound having an aromatic ring that contains a heteroatom.
The preferred meanings of A, B, D, L, E, F, G, K, I, J, K, P, Q, S, T, U, V and W are listed below in Table I.
Ή> 3 ο
>
Ρ <—I3
3 OJ
Μ Ή>3> 3
Ο>>
Ρ -Ρ
OAc
27
According to the process of the invention, the oxazinone of the formula I is converted to β -amidoesters in the presence of an alcohol and an activating agent, preferably a tertiary amine such as triethylamine, diisopropylethylamine, pyridine, N-methylimidazole and
4-dimethylaminopyridine (DMAP). For example, the oxazinones of formula I are reacted with compounds having a taxane tetracyclic ring and a hydroxyl group at C 1-4 in the presence of
4-dimethylacetopyridine (DMAP) to give compounds having a β-amido ester group at C ^ ^.
Most preferably, the alcohol is a 7-O-triethylsilylbacatin of formula III, which may be obtained as described by Green et al. in JACS 110, 5917 (19M) or other methods. As reported by Greene et al., 10-deacetylbacatin is converted to 7-O-triethylsilylbacatin of formula III according to the following scheme.
-1 6-
1 C C G H S) 3 Sl | , C, H 5 N
2. CH 2 COCl from C 5 H with N
NO. 1
a, RH b, r-coch 3
According to the conditions under consideration, the 10-deacetylbacatin of the general formula IIIa is reacted with 20 equivalents (ΛΛ II at 23 ° C under atxospheric-argen for 20 hours from <RTIgt; 1 </RTI> of 1).
to form a compound of formula (I-1) to form
7-triethylsulfonyl-1-deacetyl-ibacatin of formula (111) of the reaction product in a yield of 64 to 66% by weight
T ≥ 86% OCT (31b). Gre - no and spoi. in JAGS 110, 59> 7-5916 (1968).
How to release it in the following. Reaction Scheme 7 may triethvls1Ivl-C-111-baccatin of formula (31b) can be reacted with an oxazinone according přeiložerYho ^ -m wnsi zu ft * at room temperature under temperature to ignite taxolovóho intermediate které® at the C-7 and C-2 'hvdrcxvlov triethithionium and ethoxyethyl groups
-17-healing groups. These groups are then hydrolyzed under mild conditions so that ester linkage or taxol substituents are not disrupted. The synthesis of taxol from oxazinone 2 is performed as follows:
31b
TAXOL
While this scheme is directed to the natural taxol sythesis, it may be used with modifications of either oxazinone or tetracyclic alcohol, which may be derived from natural or non-natural sources, to prepare additional synthetic taxols in accordance with the present invention.
Alternatively, the oxazinone of formula (I) may be converted to the? -Amido ester in the presence of an activating agent and an alcohol other than 7-O-triethylsilyl-bakatin III to form taxol intermediates. Taxol synthesis can be accomplished using taxol intermediates according to a suitable reaction scheme.
Oxazinone alkyl groups; either alone or with the various substituents defined above are lower alkyl groups containing from one to six carbon atoms in the backbone and up to 15 carbon atoms. They may be straight-chain or branched and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl and the like.
Oxazinone alkenyl groups, either alone or with different substituents defined above, preferably represent lower alkenyl containing from two to six carbon atoms in the backbone and up to 15 carbon atoms. They may be straight-chain or branched and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl and the like.
-19Oxazinone alkynyl groups, either saaot or with the above-mentioned! substituents are lower alkynyl groups containing from two to six carbon atoms in the backbone and up to 15 carbon atoms and may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutinyl, aryl, hexynyl and the like ·
Examples of oxazinone alkanoyloxy groups include acetate, propionate, butyrate, valeret, isobutyretyl, and the like. The most preferred group is alkanoyloxy.
The oxazinone aryl groups, either saa or other substituents, contain from 6 to 15 carbon atoms and include phenyl, ω-naphthyl or naphthyl, etc. Substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl groups, acyloxy, nitro, amino, axido, etc. Most preferred is aryl.
if the above aohou Rg and R ^ represent an oxazinone of formula 1-ΟΚθ wherein R₉ is alkyl, acyl, ketal, ethoxyethyl (EE), 2,2,2-trichlorethoxyaethyl or other hydroxyl protecting group such as acetals and ethers, e.g. ethoxyaethyl (MOM), benzyloxyaethyl, ester such as acetate group, carbonate groups such as ethyl carbonate and the like. Various hydroxyl protecting groups and their synthesis can be found in Protective Groups in Organic Synthesis by TWGreenea, John Wiley and Soas, 1981. The hydroxyl grouping groups should be readily removable under conditions that are sufficiently mild and do not interfere with the ester bond or other substituents of the taxol intermediates. R 8 is preferably ethoxyethyl or 2,2,2-trichloroethoxy methyl, and most preferably ethoxyethyl.
The preferred meanings of the oxazinone substituents R p> 3 R 5, R 8, R 8 and R 8 are as follows:
* ·
Since the oxazinone of formula (I) has several asymmetric carbon atoms, it will be apparent to those skilled in the art that the asymmetric carbon atoes of the present invention may exist in diastereoxic, races or optically active forms. All these forms are in accordance with the claims of the present invention, more specifically, the present invention includes enantiomers, diastereomers, raceate mixtures and other mixtures thereof.
The oxazinones of formula 1 can be prepared from readily available materials according to the following reaction scheme:
The arboxylic acid of formula 33 can alternatively be prepared according to the method described by Greenea et al., JACS 110, 5917 (1988). The β-lactates of formula 32 can be prepared from readily available materials as shown in the following reaction scheme wherein R 1 and R 1 are phenyl, R 6 and R 8 are hydrogen and S g is-ΟΗθ, where Ηθ is ethoxyethyl:
reagents: a) triethylamine, CH 3 CD 3 + 25 ° C, 18 h, b) 4 eq. ceric ammonium nitrate, CH 2 CN, -10 ° C, 10 ain, c) KOH,
THF, H 2 O, 0 ° C, 30 min, d) ethyl vinylether, THF, toluenesulfonic acid (cat.), 0 ° C, 1.5 h, e) CH 2 Cl 2, ether,. -78 ° C, 10 ain, benzoyl chloride, -78 ° C, 1 h.
-24Opening material is readily available. Aeylpiylacetyl chloride is prepared from glycolic acid and condensed to form a ring with an imine prepared from aldehyde and p-methoxyaniline in the presence of a tertiary amine to give 1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-one.
The p-methoxyphenyl group can be easily removed by oxidation with ceric ammonium nitrate and the acyloxy group can be hydrolyzed under standard conditions which will be apparent to those skilled in the art to give 3-hydroxy-4-arylazetidin-2-one.
The 3-hydroxyl group may be protected by various conventional protecting groups such as 1-ethoxyethyl. Preferably, the raceate 3-hydroxy-4-arylazetidin-2-one is cleaved by pure end-endomers prior to protection by recrystallization of the appropriate 2-methoxy-2- (trifluoromethyl) phenylacetic esters and only the dextrorotatory enantiomer is used for the preparation of taxol. 1-ethoxyethoxy) -4-phenylazetidine-2-one converted to the N-lactam of formula 32 by treatment with a base, preferably n-butyllithium and aroyl chloride at -78 ° C or below.
The following examples serve to illustrate the invention and do not limit it in any way.
Example 1
Preparation of cis-2,4-diphenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one, cis-1-p-Methoxyphenyl-3-acetoxy-4-phenylazetidin-2-one .
To a solution of 962 mg (4.56 mmol) of imine derived from benzaldehyde and p-methoxyaniline and 0.85 mL (6.07 mmol) of triethylamine
- 25 ml of a solution of 413 mg (3.04 mmol) of PQ-acetoxyacetyl chloride in 15 ml of CH 2 Cl 2 are added dropwise in 15 ml of CH 2 Cl 2 at -20 ° C · The reaction mixture is allowed to warm to 25 ° C within 18 hours · The reaction mixture was then diluted with 100 mL of CH 2 Cl 2 and extracted with 30 mL of 10% aqueous hydrochloric acid. The organic layer was washed with 30 mL of water and 30 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and concentrated to give a solid which was triturated with 50 mL of hexane and filtered. The residual solid was recrystallized from ethyl acetate / hexane to give 645 mg (68%) of cis-p-methoxyphenyl-3-acetoxy-4-phenylazetidin-2-one as white crystals, mp 163 ° C.
cis-3-Acetoxy-4-phenylazetidin-2-one.
To a solution of 20.2 g of cis-1-p-methoxyphenyl-3-acetoxy-4-phenylazetidin-2-one in 700 ml of acetonitrile is slowly added a solution of ceric ammonium nitrate in 450 ml of water over 1 hour. The mixture was stirred at -10 ° C for 30 minutes and diluted with 500 mL of ether. The aqueous layer was extracted with two 10 mL portions of ether and the combined layers were washed with two 100 mL portions of water, two 100 mL portions of saturated sodium bisulfite, two 10 mL portions of saturated aqueous sodium bicarbonate, and concentrated to give 18.5 g of solid. Recrystallization of the solid from acetone / hexane yielded
12.3 g (92%) of cis-3-acetoxy-4-phenylazetidin-2-one as white crystals, mp 152-154 ° C.
cis-3% hydroxy-4-phenylazetidin-2-one.
To a mixture of 200 mL of THF and 280 mL of 1 M aqueous potassium hydroxide
At 0 ° C, a solution of 4.59 g (22.4 mmol) cis-3-acetoxy-4-phenylazetidin-2-one in 265 mL THF was added via a dropping funnel over 40 minutes. The solution was stirred at 0 ° C for 1 hour and 100 mL of water and 1OM saturated sodium bicarbonate were added. The mixture was extracted with four portions of 200 mL of ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated to give 3.54 g (97%) of racemic cis-3-hydroxy-4-phenylazetidin-2-one as white crystals. mp 147-149 ° C. This material was resolved into its enantiomers by recrystallization of its 2-methoxy-2- (trifluoromethyl) phenyl esters from hexane / acetone followed by hydrolysis (77 °).
cis-3- (1-Ethoxyethoxy) -4-phenylazetidin-2-one.
To a solution of 3.41 g (20.9 mmol) cis-3-hydroxy-4-phenylazetidin-2-one in 15 mL THF at 0 ° C was added 5 mL ethyl vinyl ether and 20 mg (0.2 mmol) methanesulfonic acid. Stir the mixture at 0 ° C for 20 minutes, dilute with 20 mL of saturated sodium bicarbonate and extract three times with 40 mL portions of ethyl acetate. Dry the combined ethyl acetate layers over sodium sulfate and concentrate to give 4.87 g (99%) of cis-. 3-d-ethoxyethoxy) -4-phenylazetidin-2-one as a colorless oil. cis-1-Benzoyl-3- (1-ethoxyethoxy) -4-phenylazetidin-2-one.
To a solution of 2.35 g (10 mmol) cis-3- (1-ethoxyethoxy) -4-phenylazetidin-2-one in 40 mL THF was added 6.1 mL (10.07 mmol) of a 1.65 M solution at -78 ° C. n-butyllithium in hexane. The mixture was stirred at -78 ° C for 10 minutes and a solution of 1.42 g (10.1 mmol) of benzoyl chloride in 10 mL of THF was added. The mixture was stirred at -78 ° C for 1 hour and diluted with 70 mL of saturated aqueous sodium bicarbonate solution and extracted three times with 5% portions of ethyl acetate. Dry the combined ethyl acetate extracts over sodium sulfate and concentrate to give 3.45 g as an oil. Chromatography of the oil on silica gel eluting with ethyl acetate / hexane gave 3.22 g (95%) of cis-1-benzoyl-3- (1- ethoxyethoxy)
4-Phenylazetidin-2-one as a colorless oil. 2R, 3S-N-Benzoyl-O- (1-ethoxyethyl) -3-phenylisoserine.
To a solution of 460 mg (1.36 mmol) of cis-1-benzoyl-3- (1-ethoxyethoxy) -4-phenylazetidin-2-one in 20 mL of THF at 0 ° C was added 13.5 mL of a 1M aqueous solution ( 13.5 mmol) of potassium hydroxide.
rt. The mixture was stirred at 0 ° C for 10 minutes and the THF was evaporated. The mixture was partitioned between 12 mL of a 1N aqueous hydrochloric acid solution and 30 mL of chloroform. The aqueous layer was extracted twice with 30 mL portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and concentrated to give 416 mg (66%) of 2R, 3S-N-benzoyl-O- (1-ethoxyethyl) -3-phenylisoserine (formula 33 wherein a R 4 is phenyl and tert-butyl). , e ethoxyethyl).
eis-2,4-diphenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one (Formula ZJ).
To a solution of 416 mg (1.16 mmol) of 2R, 3S-N-benzoyl-O- (1-ethoxyethyl) -3-phenylisoserine in 20 mL of THF was added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture is stirred at 25 ° C for 30 minutes. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF was added to the mixture and stirred at 25 ° C for 1.5 hours. The mixture was diluted with 80 mL of hexane and ethyl acetate, and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated
256 mg (65%) of cis-2,4-difeny1-5- (1-ethoxyethoxy) -4,5-dihydro1,3-oxazin-6-one of formula II as a colorless oil / 0 (/ 2 ^ «
Hg
-22 ° (CHCl 3 c = 1.55).
Example 2
Taxol preparation
To a small reaction flask was charged 77 mg (0.218 mmol) of (- Is-2,4-diphenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one (Formula II), 7-O-triethylsilylbacatin 4 (4 mg, 0.057 mmol) of 4-dimethylaminopyridine (DMAP) (6.9 mg, 0.057 mmol) and pyridine (0.029 mL). The mixture was stirred at 25 ° C for 12 h and diluted with ethyl acetate (100 mL). The ethyl acetate solution was extracted with 20 ml of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated, filtered through a plug of silica gel and eluted with ethyl acetate, flash chromatography on silica gel, eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane. ethyl acetate / hexane gave 46 mg (77%) of 2 * O * (1-ethoxyethyl) -7-O-triethylsilyltaxol as a roughly 2: 1 mixture of diastereomers and 9.3 mg (23%) of 7-O-triethylsilylbacatin of formula III: The yield based on the spent 7-O-triethylsilylbacatin of formula III is quantitative.
mg of a 2 * - (1-ethoxyethyl) -7-O-triethylsilyltaxol sample is dissolved in 2 ml of ethanol and 0.5 ml of a 0.5% aqueous hydrochloric acid solution is added. S m EC was stirred at 0 ° C for 30 ha diluted with 50 mL of ethyl acetate, extracted with 20 ml of saturated aqueous sodium bicarbonate solution *
Dry over sodium sulfate and concentrate. The residue was purified by column chromatography on silica eluting with ethyl acetate / hexane to give 3.8 mg (ca. 90%) of taxol, identical to the authentic sample in all respects.
Example 2
Preparation of N-debenzoyl-N-tert-butoxycarbonyltaxol
2. Perbutoxy-4-phenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one.
To a solution of 409 mg (1.16 mmol) of N-tert-butoxycarbonyl-O-30 (1-ethoxyethyl) -3-phenylisoserine (3) in 20 mL of THF was added 261 mg (2.33 mmol) of solid potassium tert-butoxide. and the mixture was stirred at 25 ° C for 30 minutes, and a solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF was added and the mixture was stirred for 1 h.
was stirred at 25 ° C for 1.5 hours. The mixture was diluted with 80 mL of hexane and ethyl acetate, and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. Dry the organic phase over sodium sulfate, concentrate to give 235 mg (70%) of 2-tert-butoxy-4-phenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
N J N ebenzoyl terc.butoxykarbonyltaxol.
in
A small reaction flask was charged with 73 mg (0.218 mmol) of 2-tert-butoxy-4-phenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7- O-triethylsilylbacatin III, 6.9 mg (0.057 mmol) of 4-dimethylaminopyridine (DMAP) and 0.029 ml of pyridine. The mixture was stirred at 25 ° C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 ml of 10% aqueous sodium sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through a short plug of silica gel eluting with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization yielded 44 mg (73%) of N-debenzoyl-N-tert-butoxycarbonyl-2 - (1-ethoxyethoxy) -7-triethylsilyltaxol from ethyl acetate / hexane as about 1: 1 mixture of dissers and 9.3 Mg (23%) of 7-O-triethylsilyl baccatin III.
Dissolve -315 mg of the sample of N-debenzoyl-N-tert-butoxycarbonyl-2 '- (1-ethoxyethoxy) -7-O-triethylsilyltaxol in 2 ml of ethanol and add 0.5 ml of 0.5% aqueous hydrochloric acid. The mixture was stirred at 0 ° C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 3.8 mg (ca. 90%) of N-phenoxybenzyl-N-tert. butoxycarbonyltaxol.
Example 4
Preparation of N-debenzoyl-N-tert-butoxycarbonyl-2 (1-ethoxyethyl) -3 * -phenyltaxol tBuO,
OEE
2 h tBuC ^ 2 xO
T v
0 '^ OEE
2-tert-butoxy-4,4-diphenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one.
To a solution of 497 mg (1.16 mmol) of N-tert-butoxycarbonyl-O (1-ethoxyethyl) -3,3-diphenylisoserine (3) in 20 mL of THF was added 261 mg (2.33 mmol) of solid tert. potassium butoxide and the mixture is stirred at 25 ° C for 30 minutes. Methanesulfonyl chloride (134 mg, 1.16 mmol) in THF (3.2 mL) was added and the mixture was stirred at 25 ° C for 1.5 hours. The mixture was diluted with 80 mL of hexane and ethyl acetate, and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. Dry the organic phase over sodium sulfate and concentrate to give 243 mg (59%) of 2-tert-butoxy-4,4-diphenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazine 6 -on as a colorless oil.
N-Debenzoyl-N-tert-butoxycarbonyl-3H-phenyltaxol.
Place 90 mg (0.218 mmol) in a small reaction vessel.
2-tert-butoxy-4,4-diphenyl-5- (1-ethoxyethoxy) -4,5-dihydroth, 3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilylbacatin III, 6.9 mg (0.057 mmol). 4-dimethylaminopyridine (DMA?) And 0.029 ml pyridine. The mixture was stirred at 25 ° C for 12 hours
-33 h and diluted with 100 mL ethyl acetate. The ethyl acetate solution was extracted with 20 ml of a 10% aqueous solution of copper sulfate, dried over sodium sulfate and concentrated, and the filtrate was filtered through a short silica gel column in ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane gave 44 mg (66%) of N-debenzoyl-N-tert-butoxycarbonyl 1-2 of - (1-ethoxyethyl) -3 * -phenyl-7 -O-triethylsilyltaxol as about 3: 1 mixture of diastereomers.
mg of a sample of N-debenzoyl-N-tert-butoxycarbonyl-2 (1-ethoxyethyl) -3-phenyl-7-O-triethylsilyltaxol was dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous HG1 was added. The mixture was stirred at 0 ° C for 30 minutes and diluted with 50 mL of ethyl acetate. The solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated, and the residue was purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 4.0 mg (ca. 90%) of N-debenzoyl-N. tert-butoxycarbonyl-3 ' -phenyltaxol.
Example 5 Preparation of 2,4-diphenyl-5- (1-ethoxyethoxy) -5-methyl-4,5-dihydro-1,3-oxazin-6-one
of a solution of 430 mg (1.16 mmol) of N-benzoyl-O- (1-ethoxyethyl) -2-methyl-3-phenylisoserine in 20 mL of THF was added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture was stirred for 30 minutes. stirring at 25 ° C for 30 minutes. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF was added and the mixture was stirred at 25 ° C for 1.5 hours. The mixture was diluted with 80 mL of hexane and ethyl acetate, and this solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. Dry the organic phase over sodium sulfate and concentrate to give 270 mg (76%) of 2,4-diphenyl-5- (1-ethoxyethoxy) -5-methyl-4,5-dihydro-1,3-oxazin-6-one as colorless oils.
Example 6 * -Methyltaxol
Add 77 mg (0.218 mmol) to a small reaction flask.
2,4-diphenyl-5- (1-ethoxyethoxy) -5-methyl-4,5-dihydroxy-1,3-oxazin-6-one, 40 mg (0.057 mmol) of 7-O-triethylsilylbacatin III, 6.9 mg (0.057 mmol) of 4-dimethylaminopyridine (DMAP), and 0.029 ml of pyridine. The mixture was stirred at 25 ° C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was poured over a short column of silica gel eluting with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane afforded 32 mg (53%) of 2 (t-ethoxy-ethyl) -3 * methyl-7-O-triethylsilyltaxol as a 1: 1 mixture. diastereomers.
mg of 2 '- (1-ethoxyethyl) -3 * -methyl-7-O-triethylsilyltaxol was dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous hydrochloric acid was added. The mixture was stirred at 0 ° C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 3.9 mg (ca. 90%) of 3 * methyltaxol.
inserts 125 mg / 0.320 mrnol /
Example 7
N-Lebenzoyl-N- (1-naphthoyl) taxol
The small reaction vessel was
2- [1-naphthyl] -4-phenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one, 45 mg (0.064 mmol) of 7-O-triethylsilyl-buffin III, 7 8 mg (0.064 mmol) of 4-dimethylaminopyridine (DMAP) and 0.32 ml of pyridine. The mixture was stirred at 25 ° C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through a plug of silica gel, eluting with ethyl acetate. Flash chromatography on silica gel was then eluted with ethyl acetate / hexane and recrystallized from ethyl acetate / hexane to give 62 mg (90%) of N-debenzoyl-N- (1-naphthoyl) -2H-methoxyethoxy-7-O- triethylsilyltaxol.
mg sample of N-debenzyl-N- [i-naphthoyl] -2 '- [1-ethoxyethoxy] -7-O-triethylsilyltaxol is dissolved in 2 ml of ethylene and 0.5 ml of 0.5% aqueous solution is added. HCl. The mixture was stirred at 0 ° C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane to give 3.9 mg (about 95%) of N-dehenzoyl-N- (1-naphthoyl) taxol.
Example 8
N-Debenzyl-N- (2-naphthyl) taxol
A small resection vessel was charged with 125 mg / 0.320 ml / min.
2- [2-naphthyl] -4-phenyl-5- [1-ethoxyethoxy] -4,5-dihydro-1,3-oxazin-6-one, 45 mg / 0.064 mol / 7-C-triethylsilyl-bacatin III, 7 8 mg (0.064 mmol) of 4-dimethylaminopyridine (DMAP) and 0.32 ml of pyridine. Stir the mixture at 25 ° C for 12 hours and dilute with 100 µl of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through silica gel, eluted with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane and recrystallization from ethyl acetate / hexane gave 64 mg (93%) of N-debenzyl-N- (2-naphthyl) -2- (1-ethoxyethoxy) -7 -O-triethylsilyltaxol.
mg sample of N-debenzoyl-N- [2-naphthoyl] -2 '- (1-ethoxyethoxy) -7-O-triethylsilyltaxol was dissolved in 2 ml of ethanol and 0.5 ml of 0.5% aqueous HCl was added. The mixture was stirred at 0 ° C for 30 h and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 ml of saturated sodium bicarbonate solution (aqueous), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / hexane to give 3.5 g (ca. 90%) of N-debenzoyl-N- (2-naphthoyl) -taxol.
Example 9
N-Bebenzoyl-N-pivaloyl-taxol
A small reaction vessel was charged with 102 mg / 0.320 mmol / well.
2-tert-butyl-4-phenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one, 45 mg (0.064 mmol) of 7-O-triethylsilyl-baccatin III, 7.8 mg (0.064 mmol) of 4-dimethylaminopyridine (DMAP) and 0.032 ml of pyridine. The mixture was stirred at 25 ° C for 12 h and diluted with 100 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate, dried over sodium sulfate, and concentrated. The residue was filtered through a plug of silica gel, eluting with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane gave 55 mg (85%) of N-debenzyl-N-pivaloyl-2 '- (1-ethoxyethoxy) -7-triethylsilyl-taxol.
A -385 mg sample of N-debenzyl-N-beeryl-2 '- (1-ethoxyethoxy) -7-O-triethylsilyltaxol was dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous HCl was added. The mixture was stirred at 0 ° C for 3 hours and diluted with 50 mL of ethyl acetate. The solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated, and the residue was purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 3.6 mg (ca. 52%) of N-debenzoyl-N-pivaloyltaxol .
Example 10
N-Debenzoyl-N-pentanoyl-taxol in a small reaction vessel is charged with 102 mg (0.320 mmol) of 2-n-butyl-4-phenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3 -Of trioxide, 45 mg (0.064 mmol) of 7-O-triethylsilyl-baccatin III,
7.8 mg (0.064 mmol) of 4-dimethylaminopyridine (ΛΡΛΡ) and 0.032 ml of pyridine. The mixture was stirred at 25 for 1 hour and diluted with 100 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through a plug of silica gel, eluting with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane gave 58 mg (89%) of N-debenzoyl-N-pentanol-2 '- (1-ethoxyethox, y) -7-O-triethane. yls and lvi taxol.
mg sample of K-debenzoyl-K-pentano-1-2- (1-ethoxyethoxy) -7-trimethylsilyl taxol was dissolved in 2 ml of ethanol and 0.5 ml of 0.5% aqueous HCl was added. The mixture was stirred at 0 ° C for 30 h and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate / hexane to give 3.6 mg (about 52%) of N-debenzoyl
-39K-pentano-l -texol.
Example 11 '-Zesphenyl-3' - (1-naphthyl) -taxo1
A 3o small reaction vessel is charged with 125 mg / 0.320 mmol / well.
2-phenyl-4- (1-naphthyl) -5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one, 45 mg (0.064 mmol) of 7-O-triethylsilylbacatin III, 7 8 mg (0.064 mmol) of 4-dimethylaminopyridine (DMA?) And 0.032 ml of pyridine. The mixture was stirred at 25 ° C for 12 hours and diluted with 100 ml of ethyl acetate. The ethyl acetate solution is extracted with 20 ml of a 10% aqueous solution of copper (II) sulfur,
dried over sodium sulfate and concentrated. The residue was filtered through a plug of silica gel eluting with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane afforded 62 mg (90%) of 2 '- (1-ethoxyethoxy) -3'-phenoxyphenyl (1-naphthyl) -7-O-triethyltaxol .
mg sample of 2 ' - (1-ethoxyethoxy) -3 ' -desenyl-3 ' - (naphthyl) -7-Z-triethylsilyltaxol was dissolved in 2 ml of ethanol and 0.5 ml of 0.5% aqueous HCl was added. The mixture was stirred at 0 ° C for 30 h and diluted with 50 mL of ethyl acetate. The solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 3.9 mg / as: 95% / 3 of -desphenyl-3 ' -I-naphthyl) xol.
Example 12 * -desphenyl-3 '- (2-naphthyl) taxol
125 mg (0.320 mmol) of 2-phenyl-4- (2-naphthyl) -5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one, 45 mg / 0.320 mmol, was added to a small reaction vessel. mg / 0.064 mmol / 7-0-triethylene Isilylbakatinu III, 7, 8 mg / 0.064 mmol / 4-dimethylaminopyridine / DMAP / a
-40ε 0.032 ml of pyridine. The mixture was stirred at 25 ° C for 12 h and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 ml of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through a plug of silica gel, eluting with ethyl acetate. flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane afforded 62 mg (90%) of 2 '- (1-ethoxyethoxy) -3'-desphenyl-4'-naphthyl / -7-0 -triethylsilyltaxol.
mg sample 2 * - (1-ethoxyethoxy) -3 * - desphenyl-3 * - (2-naphthyl) -7-O-triethylsilyltaxol is dissolved in 2 ml of ethanol and 0.5 ml of a 0.5% aqueous solution of KC1 is added. . The mixture was stirred at 0 ° C for 30 h and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated, and the residue is purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 3.9 mg (about 95%) of. * - (2-methylthio) axole.
Example 13 of -desphenyl-3 * -terc. but.yltaxol
After a small reaction vessel, 102 mg / 0.320 mmol / well was charged.
2-phenyl-4-tert-butyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one, 45 mg (0.064 mmol) of 7-O-triethylsilylbacatin III, 7.8 mg /. 0.064 mmol (4-dimethylaminopyridine / DMA?) And 0.032 ml pyridine. The mixture was stirred at 25 ° C for 12 h and diluted with 100 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through a plug of silica gel and eluted with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / nexane followed by recrystallization from ethyl acetate / hexane afforded 5 mg (89%) of 2 '- (1-ethoxyethoxy) -3-desphenyl-3'-tert-butyl-7-0 triethylsilyltaxol.
-415 mg sample of 2 < '- / 1-ethoxyethoxy / -J * -desřenyl of 5-tert. of butyl-7-O-triethylsilyltaxol was dissolved in 2 ml of ethanol and 0.5 ml of 0.5% aqueous HCl was added. The mixture was stirred at 0 ° C for one hour and diluted with 50 mL of ethyl acetate. The solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 3.6 mg (about 92%) of 3-desphenyl-3-tert-butyltaxol.
Example 14
3 ' -desphenyl-3 ' -p-methoxyphenyltaxol
118 mg (0.320 mmol) of 2-phenyl-4-p-methoxyphenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one, 45 mg (0.064 mmol) was charged into a small reaction vessel. 7-O-triethylsilylbacatin III, 7.8 mg (0.064 mmol) of 4-dimethylaminopyridine (DMPa) and 0.032 ml of pyridine. The mixture was stirred at 25 ° C for 12 hours and diluted with 10 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate, dried over sodium sulfate, and concentrated. The residue was filtered through a plug of silica gel eluting with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane afforded 58 mg (87%) of 2 '- (1-ethoxyethoxy) -3-desphenyl-3-p-methoxyphenyl-7-O-triethylsilyltaxol.
mg sample of 2 '- / 1-ethoxyethoxy z' * -3 * -desfenyl -pmethoxyf-3-phenyl-7-O-triethyl-sil.yltaxolu was dissolved in 2 ml of ethanol and 0.5 ml of aqueous 0.5% HCl solution. The mixture was stirred at 0 ° C for 30 hours and diluted with 50 mL of ethyl acetate. The solution is extracted with 20 ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 3.6 mg (about 90%) of 3'-isophenyl-3'-methoxyphenyltaxol.
Example 15
N-debenzoyl-N- (2-naphthyl) -3-thiophene-1,3-naphthyl-taxol
140 mg (0.320 mmol) of 2- (2-naphthyl) -4- (1-naphthyl) -5- (1-ethoxyethoxy) -4,5-dih, ydro-1,3-oxezin-6 was introduced into a small reaction vessel. -on-7-triethylsilylbacatin III, 7.8 mg (0.064 mmol) of 4-dimethylaminopyridine (DMAP) and 0.032 ml of pyridine. The mixture was stirred at 25 ° C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution was extracted with 20 mL of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through a plug of silica gel and eluted with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane gave 51 mg (70%) of N-debenzoyl-N- (2-naphthoyl). ethoxyethoxy) -3'-desphenyl-3 '- [(1-naphthyl) -7-O-triethyl silyltaxol.
mg sample of N-debenzoyl-N- (2-naphthoyl-yl) -2- (1-ethoxyethoxyl) -3'-desphenyl-3- (1-naphthyl) -7-triethylsilyltaxol dissolved in 2 mL of ethanol and 0.5 mL of 0.5% aqueous HCl is added. The mixture was stirred at 0 ° C for 30 h and diluted with 50 mL of ethyl acetate. The solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 3.3 mg (about 80%) of N-debenzoyl-yl. N- (2-naphthyl) -3'-desphenyl-3'-1-naphthyl / taxol.
Example 16
N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol / Taxotere /
A small reaction vessel was charged with 73 mg / 0.218 mg / 2-tert. butoxyl-4-phenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazin-6-one, 44 mg (0.057 mmol) of 7,1O-bis-O-triethylsilyl-43-baccatin III, 6 5 mg (0.057 mmol) of 4-dimethylaminopyridine (DMAP) with 0.029 ml of pyridine. The mixture was stirred at 25 ° C for 12 hours and diluted with 100 mL of ethyl acetate. The ethyl acetate solution is extracted with 20 ml of 10% aqueous copper sulfate solution, dried over sodium sulfate and concentrated. The residue was filtered through a plug of silica gel eluting with ethyl acetate. Flash chromatography on silica gel eluting with ethyl acetate / hexane followed by recrystallization from ethyl acetate / hexane afforded 45 mg (68%) of N-debenzoyl-N-tert-butoxycarbonyl-2'-1-ethoxyethoxy / -7,1Q-bis-O- triethylsilyltaxol as a 1: 1 mixture of diastereomers.
mg of a sample of N-debenzyl-N-tert-butoxycarbonyl-2 '(1-ethoxyethoxy) -1,10-bis-O-triethylsilyltaxol are dissolved in 2 ml of ethanol and 0.5 ml of 0.5% aqueous HCl solution is added. The mixture was stirred at 0 ° C and diluted with 50 mL of ethyl acetate. The solution was extracted with 20 mL of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / hexane to give 3.2 mg (about 90%) of N-debenzyl-N-tert-butoxycarbonyl-10-deacetyltaxol.
the foregoing description is to be understood as illustrative, and various changes may not be made without departing from the scope of the invention. The specification and examples are not intended to be limiting.
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/436,235 US5015744A (en) | 1989-11-14 | 1989-11-14 | Method for preparation of taxol using an oxazinone |
| US07/603,041 US5136060A (en) | 1989-11-14 | 1990-10-30 | Method for preparation of taxol using an oxazinone |
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| Publication Number | Publication Date |
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| CZ563490A3 true CZ563490A3 (en) | 1998-01-14 |
| CZ283581B6 CZ283581B6 (en) | 1998-05-13 |
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|---|---|---|---|
| CS905634A CZ283581B6 (en) | 1989-11-14 | 1990-11-14 | Process for preparing taxol and oxazinone as intermediate for this preparation |
| CZ953136A CZ283539B6 (en) | 1989-11-14 | 1990-11-14 | Oxazinone derivative and process for preparing thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CZ953136A CZ283539B6 (en) | 1989-11-14 | 1990-11-14 | Oxazinone derivative and process for preparing thereof |
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| CZ (2) | CZ283581B6 (en) |
| DE (1) | DE69024757T2 (en) |
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Families Citing this family (101)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
| MY110249A (en) * | 1989-05-31 | 1998-03-31 | Univ Florida State | Method for preparation of taxol using beta lactam |
| US5136060A (en) * | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
| US5380916A (en) * | 1990-11-02 | 1995-01-10 | University Of Florida | Method for the isolation and purification of taxane derivatives |
| US5475120A (en) * | 1990-11-02 | 1995-12-12 | University Of Florida | Method for the isolation and purification of taxol and its natural analogues |
| CA2071160A1 (en) * | 1991-07-31 | 1993-02-01 | Vittorio Farina | Asymmetric synthesis of taxol side chain |
| US6018073A (en) * | 1991-09-23 | 2000-01-25 | Florida State University | Tricyclic taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
| US5350866A (en) * | 1991-09-23 | 1994-09-27 | Bristol-Myers Squibb Company | 10-desacetoxytaxol derivatives |
| ATE258171T1 (en) * | 1991-09-23 | 2004-02-15 | Univ Florida State | METAL ALCOXIDES |
| US5714513A (en) * | 1991-09-23 | 1998-02-03 | Florida State University | C10 taxane derivatives and pharmaceutical compositions |
| US6794523B2 (en) | 1991-09-23 | 2004-09-21 | Florida State University | Taxanes having t-butoxycarbonyl substituted side-chains and pharmaceutical compositions containing them |
| US5721268A (en) * | 1991-09-23 | 1998-02-24 | Florida State University | C7 taxane derivatives and pharmaceutical compositions containing them |
| US5728725A (en) * | 1991-09-23 | 1998-03-17 | Florida State University | C2 taxane derivaties and pharmaceutical compositions containing them |
| US5728850A (en) * | 1991-09-23 | 1998-03-17 | Florida State University | Taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
| US5284865A (en) * | 1991-09-23 | 1994-02-08 | Holton Robert A | Cyclohexyl substituted taxanes and pharmaceutical compositions containing them |
| US5739362A (en) * | 1991-09-23 | 1998-04-14 | Florida State University | Taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
| US5430160A (en) * | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
| US6335362B1 (en) * | 1991-09-23 | 2002-01-01 | Florida State University | Taxanes having an alkyl substituted side-chain and pharmaceutical compositions containing them |
| US5274124A (en) * | 1991-09-23 | 1993-12-28 | Florida State University | Metal alkoxides |
| US6011056A (en) | 1991-09-23 | 2000-01-04 | Florida State University | C9 taxane derivatives and pharmaceutical compositions containing them |
| US5998656A (en) * | 1991-09-23 | 1999-12-07 | Florida State University | C10 tricyclic taxanes |
| US5283253A (en) * | 1991-09-23 | 1994-02-01 | Florida State University | Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them |
| US6028205A (en) * | 1991-09-23 | 2000-02-22 | Florida State University | C2 tricyclic taxanes |
| US6495704B1 (en) | 1991-09-23 | 2002-12-17 | Florida State University | 9-desoxotaxanes and process for the preparation of 9-desoxotaxanes |
| US5710287A (en) * | 1991-09-23 | 1998-01-20 | Florida State University | Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them |
| US5489601A (en) * | 1991-09-23 | 1996-02-06 | Florida State University | Taxanes having a pyridyl substituted side-chain and pharmaceutical compositions containing them |
| US6005138A (en) * | 1991-09-23 | 1999-12-21 | Florida State University | Tricyclic taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
| US7074945B2 (en) * | 1991-09-23 | 2006-07-11 | Florida State University | Metal alkoxide taxane derivatives |
| US6521660B2 (en) | 1991-09-23 | 2003-02-18 | Florida State University | 3′-alkyl substituted taxanes and pharmaceutical compositions containing them |
| US5654447A (en) * | 1991-09-23 | 1997-08-05 | Florida State University | Process for the preparation of 10-desacetoxybaccatin III |
| ES2230790T3 (en) * | 1992-01-15 | 2005-05-01 | E.R. SQUIBB & SONS, INC. | ENZYMATIC PROCEDURES FOR THE RESOLUTION OF ENANTIOMERIC BLENDS OF USEFUL COMPOUNDS AS INTERMEDIATES IN THE PREPARATION OF TAXANES. |
| US5272171A (en) * | 1992-02-13 | 1993-12-21 | Bristol-Myers Squibb Company | Phosphonooxy and carbonate derivatives of taxol |
| US5254703A (en) * | 1992-04-06 | 1993-10-19 | Florida State University | Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones |
| US5254580A (en) * | 1993-01-19 | 1993-10-19 | Bristol-Myers Squibb Company | 7,8-cyclopropataxanes |
| US5294637A (en) * | 1992-07-01 | 1994-03-15 | Bristol-Myers Squibb Company | Fluoro taxols |
| US5614549A (en) * | 1992-08-21 | 1997-03-25 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| FR2696463B1 (en) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for obtaining 10-deacetyl baccatin III. |
| FR2696458B1 (en) * | 1992-10-05 | 1994-11-10 | Rhone Poulenc Rorer Sa | Process for the preparation of taxane derivatives. |
| FR2696462B1 (en) * | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for obtaining 10-deacetyl baccatin III. |
| FR2697752B1 (en) * | 1992-11-10 | 1995-04-14 | Rhone Poulenc Rorer Sa | Antitumor compositions containing taxane derivatives. |
| ES2119996T3 (en) * | 1992-11-27 | 1998-10-16 | Napro Biotherapeutics Inc | INJECTABLE COMPOSITION INCLUDING FACLITAXEL. |
| NZ258044A (en) * | 1992-11-27 | 1995-12-21 | Faulding F H & Co Ltd | Pharmaceutical composition comprising taxol, solubilising agent, an acid and an organic solvent |
| US5380751A (en) * | 1992-12-04 | 1995-01-10 | Bristol-Myers Squibb Company | 6,7-modified paclitaxels |
| FR2698871B1 (en) | 1992-12-09 | 1995-02-24 | Rhone Poulenc Rorer Sa | New taxoids, their preparation and the pharmaceutical compositions containing them. |
| MX9307777A (en) | 1992-12-15 | 1994-07-29 | Upjohn Co | 7-HALO-Y 7ß, 8ß-METHANE-TAXOLES, ANTINEOPLASTIC USE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
| US5973160A (en) * | 1992-12-23 | 1999-10-26 | Poss; Michael A. | Methods for the preparation of novel sidechain-bearing taxanes |
| US5646176A (en) | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
| US6339164B1 (en) | 1993-01-29 | 2002-01-15 | Florida State University | C2 substituted phenyl taxane derivatives and pharmaceutical compositions containing them |
| US6187916B1 (en) * | 1993-02-01 | 2001-02-13 | Research Foundation Of State University Of New York | Process for the preparation of taxane derivatives and β-lactam intermediates therefor |
| US6593482B2 (en) | 1993-02-01 | 2003-07-15 | Aventis Pharma S.A. | Methods for preparing new taxoids and pharmaceutical compositions containing them |
| CA2155304C (en) * | 1993-02-05 | 2010-07-20 | Charles Swindell | Syntheses of paclitaxel, analogs and intermediates with variable a-ring side chains |
| US5684175A (en) * | 1993-02-05 | 1997-11-04 | Napro Biotherapeutics, Inc. | C-2' hydroxyl-benzyl protected, N-carbamate protected (2R, 3S)- 3-phenylisoserine and production process therefor |
| US6710191B2 (en) * | 1993-03-05 | 2004-03-23 | Florida State University | 9β-hydroxytetracyclic taxanes |
| DK0687260T3 (en) * | 1993-03-05 | 2003-06-10 | Univ Florida State | Process for the preparation of 9-deoxotaxanes |
| TW467896B (en) * | 1993-03-19 | 2001-12-11 | Bristol Myers Squibb Co | Novel β-lactams, methods for the preparation of taxanes and sidechain-bearing taxanes |
| ES2232694T3 (en) * | 1993-03-22 | 2005-06-01 | Florida State University | PHARMACEUTICAL COMPOSITIONS CONTAINING A TAXAN THAT HAS A SIDE CHAIN REPLACED WITH FURILE OR TIENILE. |
| PT982302E (en) * | 1993-06-11 | 2004-07-30 | Upjohn Co | USE OF DELTA 6,7-ANTINEOPLASTIC TAXOES AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM |
| TW397866B (en) * | 1993-07-14 | 2000-07-11 | Bristol Myers Squibb Co | Enzymatic processes for the resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes |
| US6005120A (en) | 1993-07-20 | 1999-12-21 | Florida State University | Tricyclic and tetracyclic taxanes |
| US5442065A (en) * | 1993-09-09 | 1995-08-15 | Board Of Regents, The University Of Texas System | Synthesis of tetrahydroquinoline enediyne core analogs of dynemicin |
| US5880131A (en) * | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| WO1995011020A1 (en) * | 1993-10-20 | 1995-04-27 | Enzon, Inc. | 2'- and/or 7- substituted taxoids |
| US5965566A (en) * | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| US6441026B1 (en) | 1993-11-08 | 2002-08-27 | Aventis Pharma S.A. | Antitumor compositions containing taxane derivatives |
| IL127599A (en) * | 1994-01-28 | 2004-06-01 | Upjohn Co | Process for preparing isotaxol analogs |
| US5508447A (en) * | 1994-05-24 | 1996-04-16 | Board Of Regents, The University Of Texas System | Short synthetic route to taxol and taxol derivatives |
| CA2170661A1 (en) | 1995-03-22 | 1996-09-23 | John K. Thottathil | Novel methods for the preparation of taxanes using oaxzolidine intermediates |
| US5560872A (en) * | 1995-05-18 | 1996-10-01 | Lever Brothers Company | Compositions comprising oxazolidine and tetrahydrooxazine amide surfactants |
| US5675025A (en) * | 1995-06-07 | 1997-10-07 | Napro Biotherapeutics, Inc. | Paclitaxel synthesis from precursor compounds and methods of producing the same |
| US5654448A (en) * | 1995-10-02 | 1997-08-05 | Xechem International, Inc. | Isolation and purification of paclitaxel from organic matter containing paclitaxel, cephalomannine and other related taxanes |
| US5854278A (en) * | 1995-12-13 | 1998-12-29 | Xechem International, Inc. | Preparation of chlorinated paclitaxel analogues and use thereof as antitumor agents |
| US6177456B1 (en) | 1995-10-02 | 2001-01-23 | Xechem International, Inc. | Monohalocephalomannines having anticancer and antileukemic activity and method of preparation therefor |
| US5807888A (en) * | 1995-12-13 | 1998-09-15 | Xechem International, Inc. | Preparation of brominated paclitaxel analogues and their use as effective antitumor agents |
| US5840748A (en) * | 1995-10-02 | 1998-11-24 | Xechem International, Inc. | Dihalocephalomannine and methods of use therefor |
| US5688977A (en) * | 1996-02-29 | 1997-11-18 | Napro Biotherapeutics, Inc. | Method for docetaxel synthesis |
| US6107497A (en) * | 1996-02-29 | 2000-08-22 | Napro Biotherapeutics, Inc. | Intermediate for use in docetaxel synthesis and production method therefor |
| FR2745814B1 (en) * | 1996-03-06 | 1998-04-03 | Rhone Poulenc Rorer Sa | NOVEL TAXOIDS, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| CA2253513A1 (en) | 1996-05-06 | 1997-11-13 | Florida State University | 1-deoxy baccatin iii, 1-deoxy taxol and 1-deoxy taxol analogs and method for the preparation thereof |
| US5750737A (en) * | 1996-09-25 | 1998-05-12 | Sisti; Nicholas J. | Method for paclitaxel synthesis |
| DE19726146A1 (en) * | 1997-06-19 | 1998-12-24 | Basf Ag | New ß-amino and ß-azidopcarboxylic acid derivatives, their preparation and use as endothelin receptor antagonists |
| US7288665B1 (en) | 1997-08-18 | 2007-10-30 | Florida State University | Process for selective derivatization of taxanes |
| ATE234800T1 (en) | 1997-08-21 | 2003-04-15 | Univ Florida State | METHOD FOR SYNTHESIS OF TAXANES |
| US6150537A (en) * | 1997-12-12 | 2000-11-21 | Emory University | Methods for the esterification of alcohols and compounds useful therefor as potential anticancer agents |
| US6156789A (en) * | 1998-03-17 | 2000-12-05 | Rhone-Poulenc Rorer S.A. | Method for treating abnormal cell proliferation in the brain |
| US6025516A (en) * | 1998-10-14 | 2000-02-15 | Chiragene, Inc. | Resolution of 2-hydroxy-3-amino-3-phenylpropionamide and its conversion to C-13 sidechain of taxanes |
| CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| US6452024B1 (en) | 2000-02-22 | 2002-09-17 | Chaichem Pharmaceuticals International | Process for extraction and purification of paclitaxel from natural sources |
| EP1318794A2 (en) * | 2000-09-22 | 2003-06-18 | Bristol-Myers Squibb Company | Method for reducing toxicity of combined chemotherapies |
| JP2004536026A (en) | 2000-11-28 | 2004-12-02 | トランスフォーム ファーマシューティカルズ，インコーポレーティッド． | Pharmaceutical formulations containing paclitaxel, its derivatives, and pharmaceutically acceptable salts |
| US6479679B1 (en) | 2001-04-25 | 2002-11-12 | Napro Biotherapeutics, Inc. | Two-step conversion of protected taxane ester to paclitaxel |
| US6452025B1 (en) | 2001-04-25 | 2002-09-17 | Napro Biotherapeutics, Inc. | Three-step conversion of protected taxane ester to paclitaxel |
| AU2002365883A1 (en) * | 2001-11-30 | 2003-06-17 | Bristol-Myers Squibb Company | Paclitaxel solvates |
| CA2501805C (en) * | 2002-10-09 | 2012-05-22 | Phytogen Life Sciences, Inc. | Novel taxanes and methods related to use and preparation thereof |
| US6759539B1 (en) | 2003-02-27 | 2004-07-06 | Chaichem Pharmaceuticals International | Process for isolation and purification of paclitaxel from natural sources |
| US7202370B2 (en) * | 2003-10-27 | 2007-04-10 | Conor Medsystems, Inc. | Semi-synthesis of taxane intermediates from 9-dihydro-13-acetylbaccatin III |
| WO2006116532A2 (en) * | 2005-04-28 | 2006-11-02 | University Of Massachusetts Lowell | Synthesis of oligo/poly(catechins) and methods of use |
| EP2029563A4 (en) * | 2006-06-12 | 2009-12-02 | Canada Inc 6570763 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
| US7847111B2 (en) | 2006-06-19 | 2010-12-07 | Canada Inc. | Semi-synthetic route for the preparation of paclitaxel, docetaxel, and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III |
| CA2723654A1 (en) * | 2008-05-07 | 2009-11-12 | Ivax Research, Llc | Processes for preparation of taxanes and intermediates thereof |
| KR101014438B1 (en) * | 2008-09-26 | 2011-02-14 | 동아제약주식회사 | The process for preparing taxane derivatives |
| AU2011274229A1 (en) | 2010-07-02 | 2013-01-10 | Angiochem Inc. | Short and D-amino acid-containing polypeptides for therapeutic conjugates and uses thereof |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4521599A (en) * | 1983-07-11 | 1985-06-04 | The Upjohn Company | Process for the preparation of 1,3-oxazine-4-ones |
| US4549014A (en) * | 1984-09-06 | 1985-10-22 | Pennwalt Corporation | Adamantyl containing 1,4-oxazinone derivatives |
| US4631340A (en) * | 1984-09-06 | 1986-12-23 | Pennwalt Corporation | 1,4-oxazinone derivatives |
| US4552585A (en) * | 1984-10-04 | 1985-11-12 | Fmc Corporation | Herbicidal 2-(aminophenyl)methyl derivatives of 3-isoxazolidinones or 3-oxazinones |
| FR2601676B1 (en) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF TAXOL AND DESACETYL-10 TAXOL |
| FR2601675B1 (en) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | TAXOL DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US4876399A (en) * | 1987-11-02 | 1989-10-24 | Research Corporation Technologies, Inc. | Taxols, their preparation and intermediates thereof |
| GB8803114D0 (en) * | 1988-02-11 | 1988-03-09 | Bp Chem Int Ltd | Bleach activators in detergent compositions |
| FR2629818B1 (en) * | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF TAXOL |
| FR2629819B1 (en) * | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF BACCATIN III AND DESACETYL-10 BACCATIN III DERIVATIVES |
| US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
| US5136060A (en) * | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
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